Off-label Drug Use

What is off-label drug use?

In the United States new drugs are tested in clinical trials (research studies) before they are approved for use in the general public. The clinical trials are done to prove that the drug:

• Works to treat a certain medical condition
• Works the way it is expected to
• Is safe when used as directed

When the US Food and Drug Administration (FDA) is satisfied that the drug works and is safe, it and the maker of the drug create the drug label. This is not an actual label that sticks onto a bottle, but a report of very specific information about the drug. The FDA must approve this report, which is made available to all health professionals who prescribe or sell the drug.

The drug label gives information about the drug, including the approved doses and how it's to be given to treat the medical condition for which it was approved. When a drug is used in a way that is different from that described in the FDA-approved drug label, it is said to be an "off-label" use. This can mean that the drug is:

• Used for a different disease or medical condition
• Given in a different way (such as by a different route)
• Given in a different dose than in the approved label

For example, when a chemotherapy drug is approved for treating one type of cancer, but is used to treat a different cancer, it is off-label use.

Off-label is also called "non-approved" or "unapproved" use of a drug.

Is off-label drug use legal?

The off-label use of FDA-approved drugs is not regulated, but it is legal in the United States and many other countries. An exception to this is the use of some controlled substances, such as opioids (pain medicines like morphine and fentanyl). These drugs cannot legally be prescribed in the United States except for approved purposes.

While it is legal for doctors to use drugs off label, it is not legal for drug companies to market their drugs for off-label uses. This has been a hot news topic recently, as drug companies have been fined because they promoted drugs for uses not approved by the FDA. Off-label marketing is very different from off-label use.

Why are drugs used off-label?

Older, generic medicines are the ones most often used off label. New uses for these drugs may have been found and there is often medical evidence to support the new use. But the makers of the drugs have not put them through the formal, lengthy, and often costly studies required by the FDA to officially approve the drug for new uses.

Off-label drug use is common in cancer treatment. There are many reasons for this:

• Some cancer drugs are found to work against many different kinds of tumors.
• Chemotherapy treatments often use combinations of drugs. These combinations might include one or more drugs not approved for that disease. Also, drug combinations change over time as doctors study different ones to find out which work best.
• Cancer treatment is always changing and improving.
• Oncologists and their patients are often faced with problems that have few approved treatment options.
• Oncologists and their patients may be more willing to try off-label drugs than other medical specialties.

What problems are caused by off-label drug use?

Reimbursement

The biggest problem is getting insurance plans to pay for off-label drug use (reimbursement). Many insurance companies will not pay for an expensive drug that is used in a way that is not listed in the approved drug label. They do this on the grounds that its use is "experimental" or "investigational."

In cancer treatment, these issues have been largely addressed through 1993 federal legislation that requires insurance to cover medically appropriate cancer therapies. This law includes off-label uses if the treatment has been tested in careful research studies and written up in well-respected drug reference books or medical journals. In 2008, Medicare rules were changed to cover more off-label uses of cancer treatment drugs.

Still, the health insurance coverage laws and regulations are complex. If your doctor is thinking about off-label drug use, you and your doctor should carefully check your health plan's coverage. If coverage is denied the first time, it may help for the doctor to send the insurer copies of peer-reviewed journal articles or other respected sources that support the off-label use.

Legal risk

Another problem is that off-label drug use often does not reflect "standard of care" treatment. This leads to possible concern about the legal risk of prescribing off-label should a patient have an unwanted or bad outcome from the treatment.

Lack of regulation and information

The FDA does not regulate the practice of medicine. In general, once the FDA approves a drug, licensed doctors can use it for any purpose they consider medically appropriate. Off-label use can vary greatly from one doctor to another. It depends on the doctor's preferences, knowledge, and past patient experiences.

One of the biggest problems related to widespread off-label use is the lack of information about how to best use the drug beyond what was approved. One of the most reliable and easy-to-find sources of information available to health professionals, caregivers, and patients is the drug label. But the label can only contain the information that has been approved by the FDA, and it does not mention off-label uses.

The medical literature reports clinical trials, including those that are not part of the FDA approval process. This is the main source of off-label use information, although treatment guidelines may also offer options that include off-label use. Treatment guidelines are based on information from medical literature, including clinical trials, and recommend standard ways to treat certain diseases.

Lack of information on off-label drug use and outcomes may also put patients at a higher risk for medication errors, side effects, and unwanted drug reactions. It is important that the patient and doctor talk about the possible risks of using the drug and weigh them against the possible benefits.

How common is off-label drug use?

Little information is available on off-label prescribing in oncology in the US. Yet, a study done in 2008 found that 8 out of 10 cancer doctors surveyed had used drugs off-label. Off-label drug use is well-documented and very common in certain settings, such as pediatrics and HIV/AIDS care.

Studies have reported that about half of the chemotherapy used is given for conditions not listed on the FDA-approved drug label. In fact, the National Cancer Institute (NCI) has stated, "Frequently the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs." Actual off-label use is likely much higher because chemotherapy is only one aspect of cancer treatment. Studies have yet to look at all the drugs used in cancer treatment, such as anti-nausea drugs and pain medicines.

What other ways are drugs used off label in cancer treatment?

One example of off-label drug use is tricyclic antidepressants to treat certain types of pain. This old class of antidepressant drugs is approved and labeled to be used for clinical depression. Today these drugs are seldom used for depression because safer drugs are now available to treat it. But doctors have found that the tricyclics often work very well in treating certain types of pain.

Another example is lorazepam (Ativan®), an anti-anxiety drug often used as an anti-nausea drug in cancer treatment. In oncology, Ativan is most commonly given under the tongue (the sublingual route), which is also not listed on the drug label. In this case, it is being given for an off-label use and by an off-label route.