The Common, yet Unspoken, Practice of Off-Label Drug Prescribing

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Have you ever asked your doctor whether the drug they are prescribing you is FDA-approved for how they are prescribing it? When a doctor prescribes an FDA-approved drug for a disease or condition, age group, or dosage other than what it has been approved for, then it is called an unapproved, or “off-label,” use.

Off-label use is a legal and fairly common practice – one in five outpatient prescriptions in the US are for off-label use! Patients may be surprised at how common off-label prescribing is and that doctors don’t need to inform patients when they are prescribing a drug off-label.

A drug is FDA-approved for certain diseases or conditions, age groups, and dosages; it has been evaluated for safety and efficacy within those criteria in clinical studies. For those patients, the drug is deemed safe, meaning that its benefits outweigh its risks and potential side effects.

When you are normally prescribed an FDA-approved drug, you can be confident that the U.S. Food and Drug Administration (FDA) has carefully evaluated its benefits and risks, there are strong scientific data supporting its use, and there are approved physician guidelines about how to safely and effectively use the drug for the disease or condition. To get approved, the drug must be deemed safe and effective, with acceptable side effects where the benefits of the drug outweigh the potential risks.

However, doctors may prescribe a drug for a disease or condition that it is not approved for if they believe it is medically appropriate. The exception to this is that some controlled substances, such as opioids, can only be prescribed for approved circumstances.

“Many people may be surprised to know that the FDA regulates drug approval, not drug prescribing,” said G. Caleb Alexander, a medical ethics advocate and assistant professor of medicine at the University of Chicago Medical Center. “Doctors are free to prescribe any drug for any [reason they think is medically appropriate].”

So, what happens when a doctor believes a drug may be useful for another disease or condition that it is not FDA-approved to treat?

What exactly is off-label drug use?

Off-label use can describe a variety of situations for using an FDA-approved drug, including prescribing the drug for a disease or condition it is not approved for (such as giving chemotherapy for a type of cancer it is not approved to treat), giving the drug in a different formulation (for example, giving it intravenously versus its approved oral capsule form), or even prescribing it at a different dose than it’s approved for (such as taking two tablets daily rather than the approved one tablet daily dosing).

It is important to remember that, although these drugs have been FDA-approved and have known safety profiles and side effects, those are technically only known for the disease or condition, age group, and specific dosing amounts for which the drug has been tested (and is approved for). Changing any of those parameters may affect how the drug works and the side effects it can have – we can’t be sure because it hasn’t been tested under those situations.

When do the benefits outweigh the risks of off-label use?

Why a doctor may consider off-label use depends on the patient’s situation. If there are no FDA-approved drugs for their disease or condition, the only option a doctor may have is to prescribe a drug off-label. If a patient has already tried all of the approved drugs with no luck, then the doctor may look towards other approved drugs for off-label use. Off-label use may also make sense for a disease or condition closely related to that which the drug is approved for. This allows a patient to potentially benefit without having to wait for FDA approval, which is particularly important in diseases like cancer.

However, off-label use is a debated topic. Doctors highlight its use in medicine when there are no other or better options, but also know there are increased risks of a lawsuit if a patient experiences serious side effects of an off-label prescribed drug. There is a fine line between evidence-based use with strict guidelines and stifling patients’ access to novel and potentially life-saving drugs.

It is also worth noting that doctors may be unaware of or unclear on the approval status of some drugs. Alexander also highlighted that “better strategies and tools are urgently needed to inform doctors about common, off-label uses that pose the greatest harm.”

What questions to ask about off-label use

Off-label use is not, generally, the first line of treatment a doctor will try – it’s usually reserved for a “last approach.” If a doctor does suggest using a drug off-label, don’t hesitate to ask her/him why they suggest that drug and what evidence they are basing their decision off of. Understanding the potential risks versus benefits is especially important for off-label use, even though the risks and benefits may not be fully known.

It would also be helpful to talk to your health insurance provider to clarify whether or not the drug will be covered for the anticipated off-label use. Insurers may not pay for unapproved uses, resulting in higher out-of-pocket costs for the patient. Luckily, Medicare has been increasing their coverage of off-label uses of cancer drugs.

Off-label drug use may be an opportunity to learn and expand the FDA-approval guidelines as well. You can ask your doctor if there are any ongoing clinical trials that you could participate in – if your doctor is prescribing this drug to you off-label, there is likely a logical reason that is worth exploring. By studying how effective the off-label drug is under a new circumstance, a helpful discovery could be made that could lead to an FDA-approval of the drug for what was previously an off-label use.

What kinds of drugs are commonly used off-label?

As you may suspect, off-label prescribing is more common for rare disease and cancer, where approved drug options tend to be limited or non-existent. According to the American Cancer Society, “a 2008 study found that 8 out of 10 cancer doctors surveyed had prescribed drugs off-label.” A chemotherapy drug may be used off-label because it is only approved for a certain type of cancer but could potentially target other tumors. Oncologists and cancer patients tend to also be more willing to try drugs off-label as chemotherapy treatments often combine multiple drugs and drug options (or drugs that are effective against the patient’s cancer) may be limited.

The anti-anxiety drug Ativan (lorazepam) is often used off-label as an anti-nausea drug and in an off-label route (under the tongue rather than the approved oral, intravenous, or intramuscular routes) during cancer treatment.

Beta-blockers, previously FDA-approved for high blood pressure, were once so widely prescribed by cardiologists to treat heart failure that they were considered a standard of care for heart failure patients. Now, some beta-blockers are even FDA-approved to treat heart failure, pointing to the fact that it’s not uncommon for off-label uses to become FDA-approved with enough use and formal clinical studies.

Psychiatric medications are also very commonly prescribed off-label, especially for use in children, as many drugs are less commonly tested in that age group. Tricyclic antidepressants, an old class of antidepressants that are rarely used to treat depression today due to safer drug options, have been found to be effective in treating certain types of chronic pain, such as using amitriptyline as a first-line drug for fibromyalgia pain. Antipsychotics are also commonly prescribed off-label for attention deficit hyperactivity disorder (ADHD). Certain newer antipsychotics (such as aripiprazole and olanzapine) are commonly prescribed off-label for other related disorders, such as obsessive-compulsive disorder (OCD), dementia, anxiety, substance abuse, eating disorders, and insomnia.

For more drug examples and their off-label uses, Consumer Reports compiled a list of commonly prescribed off-label drugs.

Fen-Phen: an infamous off-label example

One of the most infamous off-label prescription incidents involves the combination of fenfluramine hydrochloride and phentermine (commonly known as Fen-Phen). In the 1990s, the now banned appetite-suppressing drugs were approved for short-term use to treat obesity individually – the combination was never FDA approved.

This is an unfortunate example of how much power scientific publishing and the media can have. After the results from a clinical study looking at the effects of the Fen-Phen combination therapy on weight loss were published in the Journal of Clinical Pharmacology in 1992, widespread media coverage in 1995 detailed the drugs’ dramatic weight loss effects.

Doctors began widely prescribing the Fen-Phen drug combination, with over 18 million prescriptions in 1996. Soon after, devastating side effects, including severe (and possibly deadly) heart valve abnormalities which could be long-lasting, were first detailed in a New England Journal of Medicine article in August 1997. After more cases of heart valve problems linked to Fen-Phen were reported to the FDA, two fenfluramine drugs (Pondimin and Redux) were withdrawn from the market in September 1997 (phentermine was never withdrawn).

This also led to a multi-billion-dollar lawsuit. You can read more about the Fen-Phen disaster and lawsuit in Alicia Mundy’s 2001 book Dispensing with the Truth.

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