First implemented in 1979, black box warnings highlight serious and sometimes life-threatening adverse drug reactions within the labeling of prescription drug products. These safety concerns are generally identified through the FDA’s Adverse Event Reporting System and Office of Surveillance and Epidemiology, which evaluates postmarket safety data. Sometimes, however, a black box warning is handed down right at the time when a new drug is approved.
How often are drugs with black box warnings prescribed? One study found that within a 30-month period, more than 40% of patients within an ambulatory care setting received at least 1 medication that carried a black box warning for a serious adverse drug reaction that could potentially affect them.1
Although black box warnings are not necessarily absolute contraindications, pharmacists should be aware of these safety concerns when counseling patients and making recommendations to physicians. Every pharmacist should be familiar with the following black box warnings.
1. Brilinta Raises Bleeding Risk
Ticagrelor (Brilinta) received FDA approval in 2011 to reduce the risk of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction.
Like other antiplatelet agents, Brilinta has a black box warning for causing significant and sometimes fatal bleeding. The package labeling states that Brilinta should be avoided in patients with active pathological bleeding or a history of intracranial hemorrhage.
Brilinta’s labeling also states that concomitant maintenance doses of aspirin should not exceed 100 mg. During a pivotal trial, maintenance doses of aspirin greater than 100 mg were shown to decrease the effectiveness of Brilinta.
2. Linzess Should Not Be Used in Children
Linaclotide (Linzess) is a guanylate cyclase C (GC-C) agonist indicated for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.
According to the prescribing information, Linzess is contraindicated in pediatric patients younger than 6 years and should be avoided in those aged 6 through 17 years.
In nonclinical studies, administration of a single adult dose of Linzess in young juvenile mice caused increased fluid secretion and more deaths from dehydration as a result of GC-C agonism. Because of increased intestinal expression of GC-C, children younger than 6 years may be more likely to develop significant diarrhea than older children and adults.
3. Tygacil Increases All-Cause Mortality
Tigecycline (Tygacil) is an injectable tetracycline antibiotic that was approved by the FDA in 2005. The drug carries a black box warning for increasing all-cause mortality, as it was higher in patients treated with Tygacil than comparators in a meta-analysis of phase 3 and 4 clinical trials.
Although the cause of the 0.6% difference in mortality risk (95% CI 0.1, 1.2) has not been established, the deaths generally resulted from worsening infection, complications of infection, or underlying comorbidities. As a result, Tygacil’s labeling states it should be reserved for use in situations when alternative treatments are not suitable.
4. Lamictal Causes Serious Skin Reactions
Lamotrigine (Lamictal) is an antiepileptic drug indicated for the treatment of epilepsy and bipolar disorder.
Lamictal has a black box warning for causing cases of life-threatening serious rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rash-related death. The rate of serious rash has been greater in pediatric patients than adults.
Additional factors that may increase the risk of rash include coadministration with valproate and exceeding the recommended initial dose or dose escalation of Lamictal.
Although Lamictal may also cause benign rashes, the prescribing information states that it is not possible to predict which rashes will prove to be serious or life-threatening. Therefore, the medication should be discontinued at the first sign of rash, unless it is clearly not drug-related.
5. Cigarette Smoking Raises Risk of Serious Cardiovascular Events from Combination Oral Contraceptives
Combination oral contraceptives such as Alesse, Beyaz, Loestrin, Ocella, Yaz, and Zarah include an estrogen and a progestin to prevent pregnancy.
Because cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use, the package labeling warns women older than 35 years who smoke to avoid the products. Of note, this risk increases with age and the number of cigarettes smoked.
6. Fluoroquinolones Increase Risk of Tendon Rupture
Fluoroquinolones such as levofloxacin and ciprofloxacin are associated with an increased risk of tendinitis and tendon rupture in patients of all ages.
This adverse reaction most frequently involves the Achilles tendon, which may require surgical repair. Tendinitis and tendon rupture in the rotator cuff, hand, biceps, thumb, and other tendon sites have also been reported.
This risk is further increased in patients older than 60 years, those taking corticosteroid drugs, and patients who have undergone kidney, heart, or lung transplants. Tendon rupture can occur during or after completion of therapy, as cases occurring up to several months after completion of therapy have been reported.
According to the package labeling, fluoroquinolones should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and then contact their health care provider about potentially switching to a different antimicrobial drug class.
7. Methadone Raises Risk of Respiratory Depression and QT Interval Prolongation
Methadone is a synthetic opioid analgesic indicated for the treatment of moderate to severe pain, as well as the detoxification or maintenance treatment of opioid addiction.
The drug has a black box warning for increasing the risk of respiratory depression and QT interval prolongation. The package labeling states that cardiac and respiratory death has been reported during methadone initiation and conversion from other opioid agonists.
Respiratory depression is the chief hazard associated with methadone administration. The drug’s peak respiratory depressant effects typically occur after administration and persist longer than its peak analgesic effects, particularly in the early dosing period. These characteristics can contribute to cases of drug overdose, particularly during treatment initiation and dose titration.
In addition, cases of QT interval prolongation and serious arrhythmia have been observed during methadone treatment. Most cases involve patients who were treated for pain with large, multiple daily doses of methadone, although cases have also been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
The prescribing information states that methadone for analgesic therapy in patients with acute or chronic pain should only be initiated if the drug’s potential analgesic or palliative care benefit outweighs the risks.
8. Actos and Avandia Cause or Exacerbate Congestive Heart Failure
Pioglitazone (Actos) and rosiglitazone (Avandia) are thiazolidinediones indicated for the treatment of type 2 diabetes mellitus. Both medications have been shown to cause or exacerbate congestive heart failure in some patients due to dose-related fluid retention.
The drugs’ package labeling recommends monitoring patients for signs and symptoms of heart failure after initiation and dose increases. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the medications must be considered.
9. Atypical Antipsychotics Increase Risk of Death in Elderly Patients with Dementia-Related Psychosis
In 2005, the FDA issued a black box warning for atypical antipsychotics, including quetiapine (Seroquel), olanzapine (Zyprexa), and risperidone
(Risperdal), stating that elderly patients with dementia-related psychosis who are treated with these drugs face an increased risk of death.
Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotics, revealed that drug-treated patients had between 1.6 to 1.7 times the risk of death of placebo-treated patients. Although the causes of death varied, most appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature.
Observational studies have suggested that treatment with conventional antipsychotic drugs may also increase mortality. However, the package inserts acknowledge that the extent to which these findings may be attributed to the antipsychotic as opposed to patient characteristics is not clear.
10. Antidepressants Raise Suicidality Risk2
In 2004, the FDA issued a black box warning for all antidepressants indicating an association with an increased risk of suicidal thinking, feeling, and behavior in young individuals.
This decision stemmed from a series of meta-analyses of 372 randomized clinical trials involving nearly 100,000 participants, which showed that the rate of suicidal thinking or suicidal behavior was 4% among patients assigned to receive an antidepressant, compared with 2% among those assigned to receive placebo. Subsequent age-stratified analyses showed that this increased risk was significant only among children and adolescents younger than 18 years, as there was no evidence of increased risk among adults older than 24 years, including those older than 65 years.
According to the package labeling for antidepressants, patients of all ages who are started on antidepressant therapy should be monitored closely for emergence and worsening of suicidal thoughts and behaviors. Additionally, families and caregivers should be advised of the need for close observation and communication with the prescriber.
The FDA’s decision to implement this black box warning was controversial. Many members of the medical community worried that it would do more harm than good by discouraging patients from seeking help and discouraging physicians from prescribing antidepressants when clinically indicated.
- Wagner AK, Chan KA, Dashevsky I, et al. FDA drug prescribing warnings: is the black box half empty or half full? Pharmacoepidemiol Drug Saf. 2006 Jun;15(6):369-86.
- Friedman R. Antidepressants' Black-Box Warning - 10 Years Later. N Engl J Med. 2014; 371:1666-1668October 30, 2014DOI: 10.1056/NEJMp1408480.
Timothy O'Shea, MS, PharmD
Timothy O'Shea, MS, PharmD, is a Clinical Pharmacist working at a regional health insurance plan on the east coast. Additionally he works per diem at a nationwide retail pharmacy chain. He graduated from MCPHS University - Boston in 2015 and subsequently completed a PGY-1 Managed Care Pharmacy Residency. He completed his M.S. in Health Services Administration, with a focus on Health Economics and Outcomes, in 2018. His professional interests include pharmacy legislation and managed care pharmacy. He can be followed on Twitter at @toshea125.