Off-Label or Off-Limits: Should You Use a Drug for An Unapproved Use?
Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on July 15, 2021.
Off-Label Drug Use: What Is It?
You may not realize that you have probably been prescribed a drug "off-label" at one time or another by your doctor. But what does "off-label" really mean?
"Off-label" use of a drug refers to prescribing a medication for a different purpose than those formally approved by the FDA and found in the package labeling of the drug. 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.
In a study published in JAMA Internal Medicine, researchers found roughly 1 in 10 prescriptions were written for off-label use, and of those, 80 percent were for uses lacking strong scientific evidence.
Why does off-label prescribing happen, and what kinds of questions should you ask if you're prescribed a drug this way?
Why Can Doctors Prescribe Off-Label?
The FDA approves medications that are shown to be safe and effective for a particular use. They DO NOT mandate 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. Therefore, trazodone is also used "off-label" for insomnia (trouble sleeping). However, trazodone is associated with other 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.
Off-label drug use is often a benefit. However, drugs prescribed this way should be backed by published, high quality studies showing safe and effective use.
This is not always the case. Once a drug is on the market, a manufacturer may decide against investing more time and money in additional research. Yet the drug may continue to be prescribed off-label.
Is Off-Label Drug Use Safe?
It depends. 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 evidence were 54 percent more likely to experience a side effect, such as:
which led to discontinuation of the medication.
Off-Label Drug Use in Children: More Research Needed
A doctor may prescribe a medicine off-label in children, too.
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 for medications include:
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. A study by Runmore also suggested a central repository and "online forum be developed to share novel uses of medications for pediatric patients."
The American Academy of Pediatrics (AAP) Policy Statement on Off-Label Use of Drugs in Children outlines practitioner recommendations and states that "Evidence, not label indication, remains the gold standard from which practitioners should draw when making therapeutic decisions for their patients."
Federal regulations are in place to increase pediatric drug research. According to the AAP, passage of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) has resulted in more than 500 pediatric labeling changes, which expands the knowledge base practitioners can review to make informed decisions for pediatric prescribing.
Cancer: Why is Off-Label Drug Use So Common?
Off-label drug use in cancer is common, as many cancer agents are shown to be effective against more than one type of cancer but may not have been officially FDA-approved for that use.
Some cancer patients may have limited treatment success with any of the approved drugs that target their cancer and are willing to try other options.
As with many off-label drug uses, doctors may suggest use of a drug based on high quality research studies published in peer-reviewed journals and widely accepted throughout the medical community.
FDA approves individual drugs used in cancer treatment, but does not usually approve combinations of drugs (cancer regimens). Many drugs used for cancer treatment are given together, often in 2 or 3 drug combinations, and these regimens may be considered "off-label", but are evidence-based and well-accepted by oncologists and other medical experts.
A review from Saiyed and colleagues and published in the Journal of Clinical Pharmacy and Therapeutics provided an overview of off-label drug use prevalence in oncology.
- Off-label drug use in inpatient cancer patients ranged from 18% to 41%, and 13% to 71% of adult patients received a minimum of one off-label chemotherapy drug.
- Patients with metastatic cancer and in need of palliative care received the most off label drugs.
- Off-label use that was not backed up by guidelines or drug compendia ranged from 7% to 31%. But cancer patients may select to use an off label drug due to lack of treatment options.
What Are the Drawbacks to Off-Label Prescribing?
Using a drug off-label can have some downsides, and patients should be aware of these issues.
- It may be that quality clinical studies have not 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.
- Plus, insurance may not cover the costs drug therapy or cancer regimens when used in an off-label manner.
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, rare harms can still occur, even with commonly accepted uses. Be sure to discuss off-label use of any drug with your doctor.
Harms: Antipsychotic Off-Label Drug Use
However, some antipsychotics drugs have been used off-label in elderly dementia patients, often in nursing home situations to treat behavioral issues. After an FDA review in 2005, it was determined this practice may have led to serious adverse outcomes, including death, in these older patients.
Now there is a Boxed Warning in the labeling of all antipsychotic medications alerting of increased risk of death when used in elderly patients with dementia, which is an "off-label" use.
Harms: Off-Label Codeine Use in Pediatrics
Codeine was used off-label for years for pain relief in children undergoing surgery to remove the tonsils or adenoids.
However, in 2012 and 2013 the FDA reported that children with certain liver enzymes (ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism) were at risk of serious or fatal adverse effects due to depressed breathing from normal doses of codeine.
Codeine containing products (including products that contain acetaminophen) now contain a Boxed Warning (the strongest FDA warning) and is contraindicated for pain management after surgery in children younger than 18 years of age who have undergone tonsillectomy and/or adenoidectomy.
- In addition, per the FDA in 2018, children younger than 18 years of age shouldn’t use any codeine products (including hydrocodone) to treat cough.
- Children under 12 years of age should not use codeine at all.
- Avoid the use of codeine in children 12 to 18 years of age who have other risk factors (i.e, obesity, sleep apnea) that may increase their sensitivity to the respiratory depressant effects of codeine.
Always check with your doctor or pharmacist before you use codeine in your child. Codeine use can be dangerous and can lead to depressed breathing and possible death in children.
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 and provide documentation, especially for very expensive treatments like cancer.
- Many insurers require that the off-label drug use be listed in an approved resource (a drug compendium or guidelines), a collection of drug summaries developed after the off-label research is reviewed.
- 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 additional documentation to the insurance company that supports the off-label use of the drug.
A specialty pharmacy that works with patients and insurance companies to ease the process of expensive or risky drug treatments may be able to offer assistance, as well.
Other Examples: Off-Label Drug Use
Here's a small sampling of other "off-label" drug use:
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 an obvious conflict-of-interest here, and, until studies are done by the drug maker and approved by the FDA, the use remains "off-label."
However, this is a controversial area, with recent court cases contesting that the FDA rules that halt promotion of off-label use by industry violates 1st Amendment rights to free speech.
Finally, inappropriate action is not without consequences. Off-label promotion of medications by industry representatives have led to court cases requiring payments of millions in fines by industry.
Questions: Ask to Stay Informed
In today's complicated healthcare environment, 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 for the prescribed use, and if quality 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? Can you provide studies?
- What side effects or other risks might I expect?
- Will you help intervene if my insurance rejects the claim for an off-label drug use?
Next Steps: Off-Label Drug Use
Monitoring of off-label drug use in the healthcare setting is important to document effectiveness and outcomes. Electronic medical records should 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 off-label use of a drug should be an informed decision made between a patient and their doctor considering issues such as:
- quality of scientific data
- safety and side effects
- health insurance coverage.
Research on the use of drugs in children should be a priority. Children should be prioritized as a patient group to find more approved drug uses, so that off-label drug use can be minimized. In addition, published research on combined uses of cancer treatments should be made available to patients in an understandable format.
Finished: Off-Label or Off-Limits: Should You Use a Drug for An Unapproved Use?
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