Soon after Nadine Rosendale was diagnosed with multiple sclerosis (MS), her neurologist suggested she do some homework before their next appointment, when they would pick a disease-modifying therapy. “I went to the National MS Society website and looked at the list of medications and clicked on each one,” says Rosendale, 48, a librarian from Eldersburg, MD. “I wrote down any questions, even if [they were about] words I didn't understand.”

Among the more than two dozen therapies she reviewed, Rosendale zeroed in on natalizumab (Tysabri), a monoclonal antibody drug that comes with a black box warning that it can increase the risk for progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal brain infection.

“My neurologist and I talked about it, and we decided that the benefits of taking natalizumab outweighed the risks,” says Rosendale, who has been getting monthly infusions of the drug for three years. “It's hard not to worry about the side effects, but it's important to realize that everyone is different… Just because the side effects are listed does not mean you're going to experience all of them or even any of them.”

Black box warnings—so-called because the safety information appears in a black box on a drug's packaging—are required by the US Food and Drug Administration (FDA) when a medication could cause illness or injury that may result in hospitalization or death. They may be part of the labeling when a drug is first marketed, or they may be added after information emerges from wider use of the drug or additional clinical trial data, as was the case with natalizumab. The MS drug was taken off the market for a year or so before it was reintroduced as part of an FDA drug safety program, Risk Evaluation and Mitigation Strategy (REMS), designed to ensure that the benefits of medications with serious side effects outweigh the risks. Many neurologic drugs, including some used to treat MS, epilepsy, and migraine, carry black box warnings.

“Physicians should always discuss the anticipated benefits and risks of a medication with their patients before prescribing a medication,” says Joseph Ross, MD, MHS, professor of public health at the Yale School of Medicine in New Haven, CT. “A black box warning doesn't mean the balance of benefits and risks for that patient doesn't tip toward benefit. It depends on the likelihood and severity of the risk, as well as the likelihood and magnitude of the benefit. Each patient will weigh the likelihoods differently.”

About one-third of newly approved drugs end up with a boxed warning or are the subject of an FDA safety communication after they are already on the market, says Dr. Ross, who has conducted research on the topic. One of his studies, published in the Journal of the American Medical Association in May 2017, found that of 222 novel therapies (drugs or biologics) that came to market between 2001 and 2010, 123 were the subject of a postmarket FDA safety action. About half of those (61) involved adding a boxed warning. Follow-up research by Dr. Ross and colleagues found no evidence to suggest black box warnings are becoming more common, nor do they seem to be associated with faster approval time or the size of the clinical trial done to win FDA approval.

Black box warnings are designed to inform both prescribing clinicians and patients about potential serious effects and to highlight precautions or restrictions that might reduce the chances of an adverse reaction. Women of childbearing age, for example, are not typically prescribed topiramate, an antiseizure drug with a warning about the risk of birth defects. Patients who smoke or have heart failure or are older than 80 may not be candidates for some drugs with warnings, says Dr. Ross.

Black box warnings are one of many factors that should be considered when selecting a medication, says G. Caleb Alexander, MD, co-director of the Center for Drug Safety and Effectiveness at Johns Hopkins Bloomberg School of Public Health in Baltimore.

The choice about which drug to use may differ from patient to patient with the same condition. And a patient might choose to proceed with a risky drug in certain circumstances but not others, says Dr. Alexander. Somebody with advanced cancer, for instance, may be more willing to take a chemotherapy agent that comes with dire-sounding warnings if it offers a chance for remission, but the same person may be uncomfortable taking an antibiotic with a black box warning if other antibiotics work equally well.

“Discussions about the risks and benefits of prescription drugs—including those for conditions such as MS, Parkinson's, and chronic pain—are as important as ever,” Dr. Alexander says. “New treatments continue to become available, and risks that may be included on the drug label, including black box warnings, may not be fully defined until years after their market debut.”

“I consider the warnings a communication tool to ensure that providers and patients have a better understanding of what the concerns may be,” says Brad C. Klein, MD, MBA, FAAN, director of the Headache Center at Abington-Jefferson Health in suburban Philadelphia. He commonly prescribes drugs with black box warnings, including naproxen (Aleve), venlafaxine (Effexor), and propranolol (Inderal), for his patients with migraine.

The process of selecting a medication works best when “patients and providers work together, and patients understand the pros and cons of the medication and why providers are going to use it,” says Dr. Klein. The better patients understand the rationale for taking a certain drug despite its risks, the more likely they are to take it as prescribed and allow time to see if it helps, he says.

“Patients should be aware of potential side effects,” Dr. Klein says, “but it's important to remember that drug studies are done with large groups of people.” Thus the findings, often presented as averages, do not predict how one person will respond.

Shirley Kessler, 59, had her first migraine attack when she was 24. Since then, she has had as many as 15 a month. For her, the risk of a serious side effect from a drug is no more frightening than the reality of having disabling headaches. “With as many symptoms as I have, I will try any drug that can potentially help me,” says Kessler, who lives in West Conshohocken, PA, and directs an advocacy and education organization called Miles for Migraine. Over the years, she has benefited from the “rescue drug” dihydroergotamine (DHE) and onabotulinumtoxin A (Botox), both of which have warnings.

FDA warnings could deter people from getting optimal treatment because they are worried about side effects, says William D. Gaillard, MD, chief of the divisions of child neurology, epilepsy, and neurophysiology at Children's National Hospital in Washington, DC. Antiseizure drugs, for example, often come with warnings about possible suicidal thoughts and behavior, but such side effects are not experienced uniformly by everyone who takes them.

“You have to put the warning in the context of the patient and the risk he or she has,” says Dr. Gaillard, past president of the American Epilepsy Society.

He and other doctors say that to ensure the best possible choice of medication, patients must review their medical histories with their doctors and discuss treatment goals and how much risk they are willing to assume.

If people are afraid of their disease, they may be open to drugs with less established track records, says David B. Clifford, MD, FAAN, endowed professor of clinical neuropharmacology at Washington University in St. Louis. “Others are more afraid of rare side effects that could be serious.”

Kim Eldridge, 47, an engineer from Louisville, KY, who has myasthenia gravis and other autoimmune disorders, recently had to decide how to treat a urinary infection. Her doctor recommended the antibiotic ciprofloxacin (Cipro), which carries a warning of potential tendon rupture and other complications for people with myasthenia gravis. After she and her doctor discussed ciprofloxacin's risks and benefits, Eldridge decided to proceed with it, because in the past her myasthenia gravis symptoms worsened when she had an infection. She ultimately had no notable side effects from ciprofloxacin.

Patients should alert their doctors if they have unexpected side effects. They also can report drug safety concerns to Medwatch, the FDA's adverse-event reporting program.

For Nadine Rosendale, the patient with MS, close monitoring is key to maintaining her confidence in taking natalizumab despite its black box warning for risk of PML. Because the drug is part of REMS, prescribers are advised to check patients every six months for possible complications related to PML. So far, all of Rosendale's tests for PML have been negative, her regular MRI scans of her brain looking for disease progression have shown no new lesions, and her disability has not progressed significantly, she says.

Read More

See a list of drugs that have black box warnings and that are used to treat neurologic diseases.