Cytotec (misoprostol) is a good example of why the FDA approval system may not work very well for generic drugs. Misoprostol is a synthetic version of one of the body’s own prostaglandins. Prostaglandins are small lipid molecules, which signal body cells to coordinate a wide range of activities, including inflammation, blood vessel tone, blood clotting—and the onset of labor. Prostaglandins are small lipid molecules which signal body cells 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 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.
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 its 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 the drug remains “off-label” for use in labor and delivery even though the drug has become a primary component of clinical labor and delivery. This says a lot about the FDA regulatory mechanism. It says nothing about whether the drug works safely. However, clinical experience assures safety and efficacy.
Some medications take a long time to work. Misoprostol is one of them. A 25-microgram dose, placed in the vagina, swallowed, or under the tongue, works slowly. Over several hours, the cervix softens slowly. Contractions, if they come, may not start for six or eight hours and may not become established until ten hours later. This is normal. This is the drug working the way the natural prostaglandins work.
The problem in hospital practice can be impatience. The nurse according to protocol gives a patient 25 micrograms of misoprostol, watches for an hour or two, sees nothing happening, and gives another 25 micrograms. After another hour or two, there are still no contractions, and the nurse gives a third 25 microgram dose. By the time the first dose finally takes effect, three doses of misoprostol have been given and what should have been a gentle, slow onset of labor becomes a uterine emergency (hyperstimulation) with severe contractions that do not let up, fetal distress, and sometimes uterine rupture. The drug gets blamed, but the repeated dosing and the impatience behind it is the actual cause of the hyperstimulation.
Some hospitals in earlier years pushed the dose even higher, giving patients 100 micrograms every two hours. That is four times the safe dose and three times the frequency. The harms that resulted produced the bad reputation that misoprostol carries in some quarters today. But the drug at a 25 microgram one time dose, used patiently, is one of the safest induction agents available. The drug did not change. The doctors and nurses changed the dosage, and even today the usual present-day dosing is still excessive.
Five hundred years ago, the Swiss physician Paracelsus articulated what is still the founding principle of toxicology and pharmacology. He wrote that all substances are poisons and that the dose alone makes a medication not a poison. Said more simply, any substance can be a medicine and any substance can be a poison. The difference is in the dose.
Drugs that produce miracles at one dose produce disasters at another. In the public conversations about specific drugs, misoprostol included, the dose almost never enters the discussion. Misoprostol at 25 micrograms is a careful, useful, inexpensive obstetric medication that mimics the body’s own labor-onset cascade. Misoprostol at 100 micrograms every two hours, given by hospital staff that do not understood the latent period in medications, is a uterine and fetal catastrophe waiting to happen. These are not two characteristics of the same drug. They are the same drug used in two different ways, and the consequences depend almost entirely on which way, the dose.
Off-label use of a medication is looked upon as if it were unsafe or irregular. It is not. It is how much of medicine actually works. Long latent periods are considered medication failures. They are not. Long latent periods are how slow-acting (normal) drugs behave, and the right response is patience, not repeated dosing.
Drugs are treated as if they have fixed identities. They do not. The same compound at different doses is, for all practical purposes, a different drug. The dose makes the poison and the dose, used correctly, makes the medicine.
The remedy is not complicated. Understand what off-label actually means. Understand that some drugs take time to work and that patience is part of the prescription. Understand that the dose is the whole story, that no drug is safe in any dose and no drug is dangerous in every dose. Paracelsus knew this five hundred years ago. We forget it about once every generation, and then we have to learn it again.
