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Off-Label or Off-Limits? Should You Use A Drug For An Unapproved Use?

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Off-Label Drug Use: What Is It?

You may be surprised to learn that you have probably been prescribed a medication “off-label” at one point or another by your doctor. Maybe you’ve heard of “off-label” drug use in the news, but what does this really mean?

“Off-label” use of a drug refers to prescribing a medication for a different purpose than those formally approved by the US Food and Drug Administration (FDA). It’s common, and it’s legal. The package insert (or label) describes what the drug is, how it’s used, important approval research, and possible side effects, among many other drug facts. In a study published in JAMA Internal Medicine, researchers found roughly 1 in 10 prescriptions were for off-label use, and of those, 80 percent were for uses lacking strong scientific evidence. Why does this happen, and what should you consider if you’re prescribed a drug off-label?

Why Can Doctors Prescribe Off-Label?

The FDA approves medications that are shown to be safe and effective for a particular use, but they DO NOT control how a doctor practices medicine or what drugs they prescribe for any particular illness. For example, trazodone is an FDA-approved antidepressant with drowsiness as a side effect, but is used “off-label” for insomnia (trouble sleeping). However, trazodone is associated with certain side effects – such as blurred vision, dizziness, dry mouth, and nausea – that may make the risk greater than the benefit in some patients, including the elderly.

An off-label drug use should be backed by randomized, controlled studies showing that the use is safe and effective. But this is not always the case. Once a drug is approved and on the market, many manufacturers decide not to invest the time and money in additional research. Yet the drug may be prescribed off-label.

Is Off-Label Drug Use Safe?

Much off-label drug use is considered safe because doctors are familiar with the drug in use and it’s dosing, safety, and post-approval clinical trials for the off-label use. However, as reported in JAMA Internal Medicine, when a drug is used off-label with no strong scientific evidence to back it up, there is a high risk of side effects. Researchers found patients who were prescribed off-label drugs without strong scientific evidence were 54 percent more likely to experience a side effect, such as a drug reaction, drug interaction, or allergic response, which led to discontinuation of the medicine.

Off-Label Drug Use in Children: More Research Needed

Kids are not just small adults, and this is especially true when it comes to drug treatment.

A review published in Pediatrics states that “off-label” use of drugs, defined as when the drug is used in children but has only been FDA-approved for use in adults, is all too common. Up to 79 percent of hospital medications and 56 percent of office-based drugs are used “off-label” in pediatrics. Categories in need of additional pediatric research include depression, asthma, migraine, schizophrenia and bipolar disorder. Experts say lack of industry dollars in research studies, limited nonprofit funding, and exclusion of children from clinical studies due to difficult recruitment all contribute to barriers in new pediatric approvals.

Cancer: Why is Off-Label Drug Use Common?

FDA does not usually approve combinations of drugs used for chemotherapy, just the individual drugs used in a regimen. However, off-label drug use in cancer is common, as many cancer agents are effective against more than one type of cancer but may not have been officially approved for that use. Most drugs used for cancer treatment (chemotherapy) are given together, often in 2 or 3 drug combinations. Plus, some cancer patients may fail all approved chemotherapy drugs, and are willing to use other options. As with many off-label drug uses, doctors may suggest use of the drug based on quality research studies published in peer-reviewed journals and widely accepted throughout the medical community.

What Are the Drawbacks to Off-Label Prescribing?

Using a drug off-label can have some downsides. Sometimes clinical studies may not have been done after the drug is FDA-approved that support the off-label use of the drug. In this case, not only could the drug be ineffective, it might also be associated with serious side effects. Most often a doctor prescribes a drug off-label based on research and experience that shows the drug has been found to be safe and effective for that particular use. However, harms can still occur.

Harms: An Example, Antipsychotic Off-Label Drug Use

For example, antipsychotic drugs like quetiapine (Seroquel) or olanzapine (Zyprexa) are not approved for the treatment of patients with dementia-related psychosis. However, some antipsychotics drugs have been used off-label in elderly dementia patients, often in nursing home situations to treat behavioral issues. However, after FDA review in 2005, it was determined this practice may have led to serious adverse outcomes, including death, in these patients. Now there is a Boxed Warning in the labeling of all antipsychotic medications warning of increased risk of death when used in elderly patients with dementia, which is an off-label use.

Will My Insurance Pay for an Off-Label Drug Use?

The short answer to this question is: it depends. However, it may be worth your time to research the answer. Start by calling your insurance and describing the off-label use; your doctor’s office may be able to help with this, too, especially for expensive treatments like cancer. Many insurers require that the off-label use be listed in an approved resource, which is a collection of drug summaries developed after the research is reviewed and agreed upon by experts. If your insurance will not pay for a drug or an off-label drug use, discuss other medication options with your doctor. Your doctor may also be able to submit documentation that supports the off-label use of the drug to the insurance company.

Other Examples: Off-Label Drug Use

As noted by Wittich and colleagues, off-label drug use is widespread throughout most medical specialties.

  • Diphenhydramine (Benadryl) – insomnia
  • Meperidine (Demerol) – postoperative shivering
  • Doxorubicin – Unrepsonsive Multiple Myeloma
  • Gabapentin (Neurontin ) – fibromyalgia, hiccups, hot flashes, restless leg syndrome
  • High dose amoxicillin – pediatric otitis media
  • Beta-blockers (such as propranolol) – public speaking anxiety

There are many more examples of off-label drug use, this is just a small sampling.

Pharma and Off-Label Prescribing

While it is perfectly legal for a doctor to prescribe a drug off-label, drug manufacturers may not promote such uses, either through company representative visits to doctors or by advertising. There is obvious conflict-of-interest here, and, until studies are done by the drug maker and approved by the FDA, the use remains “off-label.” Drug companies are allowed to respond to unsolicited questions about off-label use of drugs from health care providers. The information must be documented and provided via their medical affairs department, and not by the sales force.

However, this is a controversial area, with recent court cases contesting that FDA rules that halt promotion of off-label use by industry violates 1st Amendment rights to free speech. However, as noted by Good and colleagues of the Pittsburgh Veterans Affair (VA), “The FDA and courts must carefully consider these findings as they contemplate guidance that would relax regulations to permit promotion of drugs beyond their labeled indications.”

Off-label promotions of medications by industry representatives have led to court cases requiring payments of millions or billions in fines by industry. In 2012, GlaxoSmithKline paid out over $3 billion to settle court cases for off-label promotion involving the antidepressants paroxetine (Paxil) for use in children and bupropion (Wellbutrin) for weight loss. In that same year, Abbott was hit with a $1.6 billion payout for off-label promotion of valproic acid in nursing homes to control behavioral issues in older schizophrenia patients and in patients with dementia, according to BMJ.

Questions: Ask to Stay Informed

In today’s complicated healthcare arena, it’s important to be proactive in your healthcare decisions and drug treatments. Patients should discuss with their doctor if a drug is FDA-approved or not for the prescribed use, and if quality, unbiased, and independent clinical studies back up the off-label use. Examples of questions that might be useful include:

  • Why is this drug helpful when used off-label for my particular condition?
  • What other options do I have, including approved uses of other drugs?
  • How long has this drug been used for this off-label condition, and how good is the data that supports the use?
  • What side effects or other risks might I expect?
  • Will you (the healthcare professional) help intervene if my insurance rejects the claim for an off-label drug use?

Next Steps: Off-Label Drug Use

Gathering data on off-label drug use in the healthcare setting is difficult, but important, so that healthcare providers can follow effectiveness, safety and other outcomes. Electronic medical records should be developed that include capture of off-label prescribing data so as to monitor prescribing patterns and safety.

In addition, healthcare professionals should provide greater information for consumers on the benefits – or risks – of off-label drug use. The use of a drug off-label should be an informed decision made between patient and provider considering issues such as risk-to-benefit ratio, effectiveness, robustness of scientific data, alternative treatments, safety, side effects, and insurance coverage.

References

L. Anderson, PharmD; Last Updated May 12, 2016