Are Off-Label Medications Are Safe

In medicine, many drugs are used for conditions which are not specified on the label. You have probably heard the term off-label use before. When a drug is approved by the Food and Drug Administration (FDA), it is approved for a specific application, the disease or condition for which the drug was tested in the trials that led to the FDA approval. The drug company submits years of data showing that the medication is safe and effective (in theory) for that particular use, the FDA reviews the data, and the FDA approves the drug for that one use. The package insert, which comes with a prescription lists that one condition for which the drug was approved by the FDA.

Using this same drug for a different condition is what is called off-label use. The drug has not been formally evaluated by the FDA for any indication except the condition for which the FDA received an application. It does not mean the drug is untested, unsafe, or unstudied. It means the FDA’s specific stamp of approval does not extend to that particular use. There is often substantial published literature, decades of clinical experience, and broad professional consensus supporting the off-label use. At times there is more scientific literature or medical experience supporting an off-label use of a drug than supports the FDA-approved indication.

The reason most off-label uses never become approved by the FDA is economic. By current estimates, running a drug through the FDA approval process costs one to three billion dollars. Adding a new indication to an existing drug can require millions of dollars in new clinical trials because,unfortunately,the FDA does not accept existing clinical experience as a substitute for randomized controlled trial data, but it could and should.

Once a drug’s patent has expired and generic manufacturers can produce it freely, no drug company has any reason to invest millions in seeking approval for a new use of a medication. Often drugs that have proven useful, safe, and effective for many years of clinical practice remain officially off-label indefinitely, not because they are not safe and effective but because no one is willing to file the paperwork or spend the money to get approval for a generic drug when other pharmaceutical companies can produce the same drug cheaply.

The FDA is a regulatory body, but its decisions about what gets approved and what does not are shaped by political and economic pressures more than science. This is not a conspiracy. It is the predictable consequence of a system in which approval is expensive, evidence has to be packaged in a particular way, and the drug company gathering the evidence has to be able to see a future profit for stockholders and executives. The line separating approved drugs as opposed to off-label drugs is a direct result of the economics of pharmaceutical development, not the safety or effectiveness of the drug.

Misoprostol (trade name Cytotec) is a good example of this approval problem. Misoprostol is a synthetic version of one of the body’s own prostaglandins. Prostaglandins are small signaling molecules that the body produces in many tissues to coordinate a wide range of activities, including inflammation, blood vessel tone, blood clotting—and the onset of labor. The body’s own prostaglandins involved in labor are primarily prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha). They are produced by the membranes surrounding the baby and by the lining of the uterus, and they do two things: they soften and thin the cervix in preparation for delivery, and they cause the uterine muscle to contract. Prostaglandins are how the body starts labor on its own,naturally.

The FDA approved Cytotec (misoprostol) in 1988 for the prevention and treatment of gastric ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs such as aspirin and ibuprofen). That is the only FDA-approved indication for misoprostol. To this day, the official label says nothing about the use of misoprostol in pregnancy or labor except to avoid its use in pregnancy.

Misoprostol is a synthetic version of prostaglandin E1 (PGE1), modified slightly so it can be taken orally and so it has a useful duration of action. It binds to the same prostaglandin receptors that the body’s own prostaglandins bind to and it produces the same effects on the cervix and the uterus. So, when misoprostol is used to induce labor in a pregnant woman, it is not introducing some foreign chemical into her body. It is providing a small dose of the same signaling molecule the body would otherwise have produced on its own. It is mimicking the body’s own labor-onset cascade.

While misoprostol is officially indicated for stomach ulcers, it is, in practice, one of the most useful drugs in obstetrics for cervical ripening, labor induction, treatment of postpartum hemorrhage, and management of miscarriage. It has been studied in tens of thousands of women across hundreds of trials. The American College of Obstetricians and Gynecologists (ACOG) explicitly endorses the use of 25 micrograms for cervical ripening and induction. None of that has resulted in an updated FDA label because the patent on misoprostol expired long ago and no manufacturer has any economic reason to pay the FDA to add a new use for misoprostol. Hence misoprostol remains “off-label” for use in labor and delivery even though the drug has become a safe and effective primary component of clinical labor and delivery for years.

Off-label use of a medication is often viewed as if it were unsafe or irregular when it has been used safely in clinical practice for years. Some uninformed people blame a drug for being used for an off-label condition when the designation off-label simply means no one paid to file the paperwork for an FDA review.