Researchers have shown an association between the uptick in the number of novel therapeutic approvals and an increase in the incidence of black box warning labels—the FDA’s most stringent safety labeling requirements for prescription drugs, designed to inform prescribers and patients of the serious health risks associated with a drug’s use.
Experts have also shown that drugs approved through the FDA’s fast track programs—a growing trend—often require boxed warnings shortly after hitting the market.
For instance, in two 2017 studies published in JAMA and Expert Opinions on Drug Safety, researchers examined the incidence of new FDA black box warning requirements from 2001 to 2010 and 2008 to 2015, respectively. In both studies, nearly one-third of all FDA-approved novel therapeutics (27% and 29%) required new post-market boxed warnings.
With over 600 medications carrying boxed warnings and over 40% of patients in the ambulatory care setting receiving at least one medication with a black box warning, it’s important for healthcare providers to be aware of commonly prescribed drugs that carry these severe side effect warnings.
Here, we’ve compiled a list of 10 black box warnings that every physician should know about when counseling patients on drug safety and treatment. Read on to learn more.
10 to look out for
Aripiprazole (Abilify). This atypical antipsychotic is indicated for the treatment of various mental health and mood disorders, including schizophrenia, depression, and bipolar disorder. However, aripiprazole increases the risk of suicidal thoughts and behaviors in pediatric patients and young adults taking antidepressants, and increases the risk of death in elderly patients with dementia-related psychosis.
Of note, aripiprazole is not indicated for the treatment of dementia-related psychosis, but has a history of off-label use for the treatment of dementia. Furthermore, although not included in the boxed warning, the FDA warned that the drug could cause impulse-control problems, such as binge eating and compulsive gambling, in May 2016. More than 2,700 patients who experienced these extreme compulsive behaviors have filed lawsuits.
Dabigatran etexilate mesylate (Pradaxa). This commonly prescribed anticoagulant is indicated for the prevention of strokes in patients with atrial fibrillation, deep vein thrombosis, and pulmonary embolism. While dabigatran has been shown to increase the risk of serious bleeding during use, the drug’s boxed warning indicates that premature discontinuation may increase the risk of thrombotic events, such as stroke or myocardial infarction (MI), due to blood clots.
Canagliflozin (Invokana). A third-line medication to metformin, canagliflozin is prescribed to treat type 2 diabetes along with diet and exercise, and reduce the risk of major adverse cardiovascular (CV) events in adults with type 2 diabetes.
However, a recent boxed warning has indicated that patients with type 2 diabetes who have established CV disease (CVD) or are at risk for CVD may be at increased risk for lower limb amputation, specifically the toe, midfoot, and leg. To date, over 1,000 lawsuits have been filed.
Febuxostat (Uloric). Indicated for the chronic management of hyperuricemia in adults with gout, Febuxostat received a black box warning in February 2019, alerting prescribers and patients of the higher rate of CV mortality associated with the drug’s use compared with allopurinol, its most common competitor.
Dextroamphetamine-amphetamine (Adderall). This CNS stimulant is commonly used for the treatment of ADHD. Researchers have shown, however, that it is frequently used recreationally by college students and other young adults for its effects on improved concentration/focus, and also have demonstrated an association of the drug’s use with addictive behavior.
In addition to the known side effects of sleep disruption and increased risk for mental health problems—including depression, bipolar disorder, and aggressive or hostile behavior—there are also CV risks such as high blood pressure and stroke, as well as the potential for drug abuse and dependence, which have warranted a black box warning.
Alprazolam (Xanax). This sedative is used primarily for the treatment of anxiety disorders, is contraindicated in patients with glaucoma, and should never be used in patients with a history of drug abuse due to its addictive potential. Alprazolam’s boxed warning advises that concomitant use with opioids, alcohol, or other CNS depressants may cause severe sedation, respiratory disorders, coma, and even death.
In a 2017 safety communication, however, the FDA stated that buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other drugs that depress CNS:
"The combined use of these drugs increases the risk of serious side effects; however, the harm caused by untreated opioid addiction can outweigh these risks."
"Careful medication management by health care professionals can reduce these risks," the statement continued. "We are requiring this information to be added to the buprenorphine and methadone drug labels along with detailed recommendations for minimizing the use of medication-assisted treatment (MAT) drugs and benzodiazepines together.”
Hydrocodone and acetaminophen (Vicodin). This schedule II drug is used for the treatment of moderate to severe pain, largely after surgery. It earned a black box warning due to its highly addictive potential, as well as the increased risk of respiratory depression and significantly increased risk of liver damage/failure associated with its use.
Sertraline hydrochloride (Zoloft). Indicated for the treatment of major depressive disorder, OCD, PTSD, panic disorder, and social anxiety disorder, this selective serotonin reuptake inhibitor antidepressant received a black box warning due to the increased risk of suicide associated with its use in several demographics, including children, adolescents, young adults.
Ticagrelor (Brilinta). This antiplatelet medication received FDA approval in 2011, and is indicated to reduce the risk of CV death, MI, and stroke in patients with acute coronary syndrome or a history of MI. However, it secured its black box warning for causing significant and sometimes fatal bleeding. Ticagrelor should not be prescribed for patients with active pathological bleeding or a history of intracranial hemorrhage, and should not be initiated in patients undergoing urgent coronary artery bypass graft surgery.
Also included in the black box warning: Ticagrelor increases the risk of subsequent CV events upon premature discontinuation; therefore, managing bleeding events without treatment discontinuation is advised. Ticagrelor’s labeling also cautions that maintenance doses of aspirin greater than 100 mg can reduce the efficacy of ticagrelor and should thus be avoided.
Tigecycline (Tygacil). An injectable antibiotic, tigecycline is indicated for the treatment of complicated skin structure infections, complicated intra-abdominal infections, and community-acquired bacterial pneumonia in patients aged 18 years and older.
However, the tetracycline class antibacterial carries a black box warning for increasing all-cause mortality vs comparators. Thus, it should only be used for infections that cannot be treated with other medicines.
As a provider, it’s your duty to report any drug-related adverse event you observe or are informed about during patient visits.
These reports help to alert the FDA of side effects that may not be covered in a drug’s package insert, important safety information, or medication guide, and can lead to the addition of new boxed warnings.
To report an event, you can submit an electronic form, mail a report form to the agency, or call them directly (1-800-FDA-1088). Once you report an event, you can monitor the status of your report, or ask for the general information regarding adverse events associated with the therapeutic.