Has your doctor told you if you are taking a drug for an unapproved use? By unapproved we mean for an “indication” that has never received a review from the FDA. It is estimated that when teenagers go to a doctor, one third of the time they get an off label med (Pediatrics, Oct. 2019). In essence, they are participating in an experiment. Adults are frequently in a similar boat. Some experts estimate that antipsychotics, anticonvulsants and antidepressants are frequently prescribed off label to older people (Drugs & Aging, June 1, 2012). You might be surprised to learn that nearly 10 million people take gabapentin. Many of them don’t realize that they are taking it “off label.”
Does It Matter If You’re Taking an Off Label Med?
How would you know whether you are taking a medicine for an unapproved indication? Unless your doctor tells you she is prescribing an off label med you probably won’t have a clue. So what? Who cares whether a medicine has been FDA-approved for a particular indication or not? What does it even mean?
The Food and Drug Administration requires pharmaceutical companies to test their medications in randomized controlled trials prior to approval. Such studies have to prove that the medicine works better than placebo for a particular problem. They are expensive and time consuming, so companies don’t always test drugs for secondary uses. Once a drug is approved for one thing, a doctor can prescribe it for almost anything else.
That doesn’t mean drugs do not work for unapproved uses. It just means the company that developed the drug for one condition never submitted it to the FDA for another health concern. Because research is often lacking for unapproved uses, prescribers may not have decent data on effectiveness, risks or appropriate dosing.
That hasn’t stopped drug companies from promoting medications for off label uses, even though it has been illegal for decades. Billions of dollars in fines have been levied against pharmaceutical manufacturers that marketed their products in this wild west environment.
Are You Taking an Off Label Med?
Are you taking gabapentin for nerve pain, bipolar disorder or fibromyalgia? What about trazodone for insomnia or propranolol for stage fright? If so, did your doctor tell you that these uses are considered “off label”? The FDA never approved them for these purposes.
Here’s an off label med we bet you are unaware of. Sertraline (Zoloft) is one of the most frequently prescribed antidepressants in the pharmacy. But some doctors prescribe it to men who complain of premature ejaculation. They may not mention that the drug can reduce libido and make it difficult to achieve orgasm.
Gabapentin: A Popular Off Label Med
In the case of gabapentin, nearly 10 million people take this anticonvulsant annually. Most of them are taking it off label. Although FDA has also approved this seizure drug for treating postherpetic neuralgia (lingering pain after shingles), doctors frequently prescribe it for problems such as migraine headaches, anxiety, restless legs syndrome, bipolar disorder, fibromyalgia, hot flashes, hiccups and pain. All of those are unapproved uses.
Prescribers may not tell patients when they are writing an off label prescription. Take gabapentin as an example. Little research appears to support its use for migraines or fibromyalgia.
Although doctors sometimes prescribe it for depression, gabapentin comes with a warning about suicidal thoughts or behavior.
“Antiepileptic drugs (AEDs), including Gabapentin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
“Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.”
In addition, this drug can cause dizziness, drowsiness, confusion and memory problems. Are people taking gabapentin as an off label med warned about the dangers of driving?
“Patients taking Gabapentin should not drive until they have gained sufficient experience to assess whether Gabapentin impairs their ability to drive. Driving performance studies conducted with a prodrug of gabapentin (gabapentin enacarbil tablet, extended-release) indicate that gabapentin may cause significant driving impairment. Prescribers and patients should be aware that patients’ ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by Gabapentin, can be imperfect. The duration of driving impairment after starting therapy with Gabapentin is unknown. Whether the impairment is related to somnolence or other effects of Gabapentin is unknown.
“Moreover, because Gabapentin causes somnolence and dizziness, patients should be advised not to operate complex machinery until they have gained sufficient experience on Gabapentin to assess whether Gabapentin impairs their ability to perform such tasks.”
Stopping Gabapentin Suddenly?
Another rarely discussed problem is “discontinuation syndrome.” Patients who stop taking gabapentin suddenly may experience severe anxiety, sweating, nausea, insomnia, pain and seizures.
These days gabapentin is often prescribed as an addition to, or substitute for, opioids for pain. Although it has long been considered free from misuse, evidence is growing that some people do indeed abuse this drug (Clinical Drug Investigation, Aug. 2017). People who take it with an opioid specifically to get high run quadruple the risk of respiratory depression–the main cause of death due to opioids.
An overview of the unapproved use of gabapentin (Substance Abuse: Research and Treatment, Sept. 23, 2018) noted:
“Gabapentin is widely used in the United States for a number of off-label indications, often as an alternative to opioid therapy. Increasing evidence has emerged suggesting that gabapentin may not be as benign as once thought and may be associated with substance abuse in concert with opioids… Reviews on off-label indications such as migraine, fibromyalgia, mental illness, and substance dependence have found modest to no effect on relevant clinical outcomes.”
Off Label Med Prescribing: Transparency Please!
Most people who take gabapentin off label don’t know it was not FDA-approved for their problem. In that respect, they are very similar to patients taking other drugs for unapproved uses.
When the antidepressant fluoxetine (Prozac) is prescribed for premature ejaculation, that is off label. When a doctor prescribes tamsulosin to make kidney stones easier to pass, that use too is off label.
Tamsulosin (Flomax): Another Off Label Med Example:
Sometimes, when such unapproved uses are studied, they are found to be ineffective. A study of tamsulosin discovered that the drug was no better than placebo at helping people pass kidney stones (JAMA Internal Medicine, Aug. 1, 2018).
Tamsulosin (Flomax) is what pharmacologists call an “alpha-blocker.” It has FDA approval:
“…for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).
In other words, tamsulosin has a green light to help men pee if they have an enlarged prostate gland.
An article in the World Journal of Urology, Feb. 29, 2024 describes the purpose of its review of alpha blockers like tamsulosin.
“The present paper takes a different and more critical look at the role of alpha-blockers, sometimes nicknamed as ‘magical pills’, in particular for stone disease and medical expulsive therapy (MET).
“Alpha-blockers seem to be a panacea, being used to treat a wide variety of non-urological diseases and conditions. Urological applications include erectile dysfunction to benign prostatic hyperplasia, from incontinence to urinary retention, or even to facilitate urinary stone passage along the urinary tract. Due to its versatility, alpha-blockers appear to be the Swiss army knife of urological medications. However, the efficacy of alpha-blockers for MET, pain management, or facilitating upper tract access is very disappointing, bringing no, or in some instances, only marginal benefits. Their treatment results are far from being significant or impressive let alone magical.”
Occasionally, though, off-label uses are supported. Doctors prescribed ketamine for suicidal patients for a number of years before a drug company won approval for a closely related compound, esketamine (Spravato).
The Good, Bad and Ugly Side of an Off Label Med:
Sometimes a drug can work extremely well for an unapproved use. That said, patients deserve to know if a drug is being prescribed off label.
The Thalidomide Example:
Can you think of any more ugly episode in medicine than thalidomide? This drug was originally developed in Germany in the 1950s. It was considered so safe it was sold over the counter without medical supervision. The drug was taken for anxiety, insomnia and symptoms of morning sickness.
One of the first hints that there was a problem with this drug occurred on Christmas, 1956. An employee of the company that manufactured thalidomide had a baby girl who was born without ears. Eventually, thousands of children were both with severe birth defects. Many died. It was one of the worst chapters in pharmaceutical history.
Then, in the 1990s thalidomide experienced a resurrection. The FDA approved the drug under the brand name Thalomid to treat a rare form of leprosy (erythema nodosum leprosum or ENL).
Celgene, the company that received the green light to market Thalomid in 1998 had a clear path to market. Some experts estimated that fewer than 100 people in the U.S. suffered from this inflammatory form of leprosy.
The real market for Thalomid, however, was for the treatment of the blood cancer multiple myeloma. It did not take oncologists long to start prescribing Thalomid for myeloma. It was a game changer. The FDA approved Thalomid for multiple myeloma in 2006. According to the New York Times (July 25, 2017), Thalomid brought in $388 million in 2005, before the FDA gave it a green light for multiple myeloma. You can bet that most of those sales were not to patients with leprosy.
Celgene followed Thalomid’s success with a chemical cousin, lenalidomide (Revlimid). In 2016 Revlimid had sales of almost $7 billion.
Despite such success, Celgene got into trouble for off label med marketing:
“The pharmaceutical company Celgene has agreed to pay $280 million to settle claims that it marketed the cancer drugs Thalomid and Revlimid for unapproved uses, the company said on Tuesday.” New York Times, July, 25, 2017
Avastin for Macular Degeneration:
Another example is the use of the anti-cancer drug bevacizumab (Avastin) for age-related macular degeneration. Although it is not approved for this purpose, it appears to work as well as the approved medications (European Journal of Ophthalmology, online Oct. 23, 2019). The advantage? It is much less expensive.
What Should You Do About Off Label Prescribing?
When you get a prescription, ask whether it is off label. If it is, keep asking: how do you know it is effective? Do not rely on the “in my experience” explanation. Ask to see the research supporting an off label med. Make sure the prescriber is up to date on the latest data.
Doing It Yourself:
Here is a way for you to do this research yourself. Let’s say your doctor has prescribed gabapentin for fibromyalgia. Go to the website: PubMed. This is the site for the U.S. National Library of Medicine. You will see a window where you can put your question. In the case of gabapentin, put into the query:
Gabapentin fibromyalgia off label
You will find 7 articles, one being: “A Clinical Overview of Off-Label Use of Gabapentinoid Drugs” published in JAMA Internal Medicine on May 1, 2019.
Click on that link:
You will find the abstract with the following Conclusions:
“Clinicians who prescribe gabapentinoids off-label for pain should be aware of the limited evidence and should acknowledge to patients that potential benefits are uncertain for most off-label uses.”
You can show that article to your prescriber and ask if she has any data to challenge that conclusion.
Other Questions:
You will want to ask about dosing instructions for the off-label med you have been prescribed. Are they different from the indicated use? How does your prescriber know?
Ask about the possible side effects or other complications that might occur with an unapproved use? What are the alternatives? Are there any approved meds for your condition?
Ask about insurance. Many insurance companies will not pay for an off label use. That is especially true for expensive cancer drugs. Make sure your doctor is willing to appeal a rejection by the insurance company if he believes the drug is essential for your situation.
Any time you take medicine, you want to weigh benefits and risks. Off label prescriptions make that a bit more difficult.
Share Your Thoughts:
Have you ever received an off label med? How well did it work? Were you told it was being prescribed for an unapproved use? We would love to learn about your experience in the comment section below.
