What is off-label prescribing and why can doctors do it?

Off-label use 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. 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.

Doctors might prescribe medications off-label for a medical condition because the use is well-known, has been done for many years without concerns, or there is a lack of safe or effective alternatives.

Examples of off-label prescribing

• Trazodone (brand name: Desyrel) is an FDA-approved antidepressant with drowsiness as a side effect. Therefore, trazodone is sometimes prescribed "off-label" for insomnia (trouble sleeping).
• Tricyclic antidepressants like amitriptyline - neuropathic pain (nerve pain)
• Meperidine (Demerol) - postoperative shivering
• Gabapentin (Neurontin) - fibromyalgia, hiccups, hot flashes, restless leg syndrome
• Beta-blockers - anxiety, stage fright (propranolol), migraine headaches (nadolol)

Over time, off-label drug uses may eventually get approved by the FDA if there is enough research data provided to show safety and effectiveness, and a manufacturer pursues an approval.

Is off-label prescribing legal?

Off-label prescribing is legal and is commonly done by many physicians. It is also acceptable to study and publish research results for off-label uses of drugs without specific FDA approval.
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.

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."

Is off-label prescribing safe?

It depends. Much off-label drug use is considered safe because doctors are familiar with the drug in use and its dosing, safety, and post-approval clinical trials for the off-label use. Off-label use of a medicine may have been in practice for years, or even decades, without major safety concerns.

However, in a study published in JAMA Internal Medicine, researchers found about 1 in 10 prescriptions were written for off-label use, but of those, 80% were for uses lacking strong scientific evidence. They also found 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% more likely to experience a problem which led to discontinuation of the medication, such as a side effect, a drug interaction, or an allergic response.

It's important that you and your doctor evaluate the risk vs. benefit of prescribing a drug for off-label use.

What are the drawbacks to using a drug off-label?

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 of expensive drug therapy, including cancer regimens, when used in an off-label manner.
• There may be limited information for the patient to review before use of the medicine for a particular condition.

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.

Examples of dangerous off-label drug use

Two examples of drugs or classes where off-label prescribing has led to harms includes the antipsychotic drug class for dementia in the elderly and the use of codeine in children.

Antipsychotics

Antipsychotics drugs were used off-label in elderly dementia patients, often in nursing home patients, to treat behavioral issues. However, after an FDA review in 2005, it was determined this practice may have led to serious adverse outcomes, including death, in these older patients.

• For example, antipsychotic drugs like quetiapine (Seroquel) or olanzapine (Zyprexa) are not approved for the treatment of patients with dementia-related psychosis.
• Antipsychotic use may increase the risk of death in older adults with dementia-related psychosis.
• Now, an FDA-mandated Boxed Warning is on the labeling of all antipsychotic medications alerting of the increased risk of death when used in elderly patients with dementia, which is an "off-label" use.

Codeine

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. It is contraindicated in package labeling.
• Avoid the use of codeine in children 12 to 18 years of age who have other risk factors (i.e, obesity, sleep apnea, other lung problems) 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.

What should I ask my doctor about off-label use of drugs?

Patients should discuss with their doctor if a drug is FDA-approved for the prescribed use, and if not, do quality clinical studies back up the off-label use.

Examples of questions that would 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 the 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?

This is not all the information you need to know about off-label use for safe and effective use of medicines and does not take the place of your doctor’s directions. Discuss this information and any questions you have with your doctor or other health care provider. Be sure to discuss off-label use of any drug with your doctor. Do not stop any medication without speaking to your doctor first.