Lifeguards warn swimmers of hazardous conditions by flying red flags on the beach. The police use flares to alert motorists to an accident on the road ahead. Weather forecasters categorize hurricanes from 1 to 5. (Hurricane Irma grabbed everyone’s attention because wind speeds of 157 mph made it a Cat 5 storm.) The FDA relies on black box warnings in the official prescribing information to alert prescribers and patients that certain drugs pose very high-risk dangers. There is nothing stronger than a black box warning when it comes to medications.
What Is a Black Box Warning?
If you look at the “package insert” for such a drug, you will find a literal box at the top of the first page. Inside the black border is a notice about serious or even life-threatening problems the drug may cause. It is the strongest warning the FDA uses, comparable to a lifeguard’s red flag.
In many cases, serious reactions to drugs are identified only after the medicine has been approved and on the market for some time. A study conducted at the University of California, San Francisco, found that “boxed warnings are common, affecting more than one-third of recent drug approvals” (JAMA Internal Medicine, Oct., 2014). More than 40 percent of the boxed warnings were added only after the drug had been on the market for years (the median was four years).
Having people take such medicines before we know their true hazards would be like allowing swimmers and surfers out into the waves as a hurricane (like Irma) approaches. They won’t be aware of the dangerous rip tides and undertows such a storm may create.
When a Warning Is Added
The problem is that many health professionals may not realize a drug they have been prescribing or dispensing for a long time has a new and serious warning added. Although they may initially study the side effects of a new drug carefully, once they are accustomed to relying upon it for patients they may not go back and reread the prescribing information.
A study of prescribing habits found that doctors often overlooked black box warnings for patients over 65 (American Journal of Managed Care, Nov. 1, 2009). Here is the conclusion.
“Administrative claims analysis identified low rates of prescriber compliance with BBWs [black box warnings] in managing patients age ≥65 years.”
Older people are often more vulnerable to serious side effects, so highlighted cautions are critical and should not be ignored.
Amiodarone Dangers
Take the heart rhythm drug amiodarone (Cordarone, Pacerone). The boxed warning states: “Amiodarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity.” The FDA goes on to describe “potentially fatal toxicities” including lung damage, liver injury and heart rhythm disturbances.
One reader reported a tragic story:
“My dad recently died after going into the hospital for pneumonia. It was discovered he had lung disease due to taking amiodarone for many years. He was never warned about the side effects from this drug. He was otherwise a very healthy man.”
This patient should have been told about symptoms to watch for so that action could have been taken before it was too late. That is the whole point behind the boxed warnings.
Surprising Black Box Warnings:
More than 400 medications come with a black box warning (Journal of General Internal Medicine, June, 2011). Some familiar examples include the arthritis drug celecoxib (Celebrex), the antidepressant venlafaxine (Effexor) and the antibiotic levofloxacin (Levaquin). If you ever took one of these drugs, did anyone ever alert you to the black box warning?
Celebrex (celecoxib) Black Box Warning:
WARNING:
Cardiovascular Thrombotic Events
“Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use. CELEBREX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.”
Gastrointestinal Bleeding, Ulceration, and Perforation
“NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious (GI) events.”
Effexor (venlafaxine) Black Box Warning:
BOXED WARNING
Suicidality and Antidepressant Drugs
“Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of venlafaxine tablets, USP or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need… Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber…”
Most antidepressants come with similar warnings. We wonder how carefully prescribers are about mentioning these concerns when they prescribe one of these drugs.
Levaquin (levofloxacin) Black Box Warning:
WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS
“Fluoroquinolones, including LEVAQUIN, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together, including:
- Tendinitis and tendon rupture
- Peripheral neuropathy
- Central nervous system effects
Discontinue LEVAQUIN immediately and avoid the use of fluoroquinolones, including LEVAQUIN, in patients who experience any of these serious adverse reactions
Fluoroquinolones, including LEVAQUIN®, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid LEVAQUIN in patients with a known history of myasthenia gravis
Because fluoroquinolones, including LEVAQUIN, have been associated with serious adverse reactions, reserve LEVAQUIN for use in patients who have no alternative treatment options for the following indications:
- Uncomplicated urinary tract infection
- Acute bacterial exacerbation of chronic bronchitis
- Acute bacterial sinusitis”
Central Nervous System Effects?
The black box warning for Levaquin and similar fluoroquinolone antibiotics mention “central nervous system effects.” What the heck does that mean? Here are the details:
“convulsions, toxic psychoses, increased intracranial pressure (including pseudotumor cerebri). Fluoroquinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, and insomnia. Suicidal thoughts, and attempted or completed suicide may also occur, especially in patients with a medical history of depression, or an underlying risk factor for depression. These reactions may occur following the first dose.”
People’s Pharmacy Perspective:
We just scratched the surface of black box warnings. Patients need to check on the drugs they are taking, since physicians and pharmacists don’t always take the time to see if new warnings have been added to the prescribing information. To help facilitate this conversation, we offer a free drug safety questionnaire and medical history form on our website, PeoplesPharmacy.com. You may also be interested in our book, Top Screwups Doctors Make and How to Avoid Them.
