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General Overview of Boxed Warnings Issued by the FDA

General Overview of Boxed Warnings Issued by the FDA

The term 'boxed warning' or 'black box warning' refers to the warning that is provided on the package inserts of certain prescription drugs. It is called a black box warning because the warning is shown within a box with a black border. This WellnessKeen write-up presents a general overview of boxed warnings issued by the FDA.
Smita Pandit
The Food and Drug Administration (FDA) launched the MedWatch Safety Information and Adverse Event Reporting System (AERS) in 1993 to encourage reporting of adverse drug reactions (ADRs) by healthcare professionals and patients.

While medications can be lifesavers, they can also be associated with certain side effects. Physicians are usually in the favor of prescribing a drug if its benefits outweigh the risks involved. The nature of the side effects is often considered when the physician determines the dosage of the drug and the duration for which the medication is prescribed. At times, the manufacturers are asked by the FDA to feature a black box warning on the label or the package insert of the medication. The need for a black box warning on a drug is felt when serious side effects are associated with the use of the particular drug.

Over the years, the FDA has asked the manufacturers of several drugs to carry such warnings. For instance, the package insert of warfarin carries a boxed warning that mentions the risk of bleeding to death. While a black box warning is the strictest form of warning issued by the FDA, it is up to the physicians to decide whether they should prescribe the drugs that carry such a warning. In cases where several clinical trials and studies show that the risks associated with a drug are very high, the FDA might even choose to withdraw the drug from the market for safety reasons.

When Does the FDA Issue a Black Box Warning?

Though a drug is approved by the FDA after analyzing the results of several studies and trials, post-market safety evaluation is also conducted by the FDA's Office of Surveillance and Epidemiology. Besides the evaluation, reports of adverse reactions are submitted to the FDA by consumers, as well as drug manufacturers, healthcare professionals, and pharmacists. FDA's Adverse Event Reporting System looks into these reports. If there are serious safety concerns, then representatives from FDA, Office of Surveillance and Epidemiology, and the Office of New Drugs decide whether the drug requires a boxed warning or not.

What Does a Black Box Warning Look Like?

A boxed warning is the most serious type of warning that is imposed by the Food and Drug Administration (FDA) for prescription medications. These warnings highlight adverse effects that could be potentially fatal. According to the FDA, these warnings must be separated from other information on the package insert. While the safety concerns that are not that serious are included in the 'Warnings and Precautions' section of the package insert, serious warnings are enclosed within a box that has a black border. Therefore, these are referred to as boxed warnings or black box warnings. Boxed warnings might also include information pertaining to the restriction of use and/or distribution of medications. Given below is the boxed warning that comes with the package insert of the drug, Warfarin Sodium.


Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR). Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age≥65, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS), and long duration of warfarin therapy. Regular monitoring of INR should be performed on all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed about prevention measures to minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding (see PRECAUTIONS: Information for Patients).

Boxed warnings are issued when the adverse reaction is potentially fatal or disabling, and the risks of the drug outweigh its benefits. For instance, the warning on iron dextran injections mentions the risk of a life-threatening anaphylactic reaction. Though the administration of iron dextran injection could cause anaphylaxis, its use might be considered when the patient is affected by severe anemia, and is not responding to oral iron supplements.

A boxed warning might be provided when there is a serious adverse reaction that can be prevented or reduced in severity by appropriate use of the drug. For instance, the warning might mention about the need to avoid the drug in specific situations. Certain drugs are beneficial for the treatment of certain conditions, but they need to be completely avoided by people affected by certain medical conditions or women who are pregnant. The need for careful monitoring of the patient might be required in some cases.

Certain boxed warnings mention restrictions regarding the administration of drugs by healthcare professionals. For certain drugs, the healthcare professionals need to complete a certification program, whereas some drugs can only be administered in supervised or inpatient settings.

Drugs With a Boxed Warning

A study conducted by Lasser and colleagues revealed that boxed warnings were imposed by the FDA within 7 years of the introduction of the drug to the market. As per their study, 10% of the 548 new medications introduced from 1975-1999 received a new black box warning or were withdrawn from the market. They suggested that the rate of boxed warnings for new medications in the next 25 years would approach 20%.

The main objective behind the black box warnings is to provide critical information to physicians. Some boxed warnings apply to individual drugs, and others apply to entire classes. According to the American Academy of Family Physicians, boxed warnings have been provided in case of the following class of drugs due to the risk of serious adverse effects:

Aminoglycosides, injectable (Tobramycin, Gentamicin) due to ototoxicity and nephrotoxicity

Angiotensin-converting enzyme inhibitors (Enalapril, lisinopril) and Angiotensin receptor blockers (Irbesartan, valsartan) for injury or death to developing fetus

Beta blockers (Metoprolol, atenolol) for the exacerbation of angina and the risk of a heart attack with abrupt discontinuation

Calcineurin inhibitors, topical (Pimecrolimus cream, tacrolimus ointment) for malignancy (causation not proven); avoid continuous long-term use; not indicated for use in patients younger than two years

Loop diuretics (Furosemide, bumetanide) for volume and electrolyte depletion

Estrogen (Estradiol in various preparations) for myocardial infarction, stroke, deep venous thrombosis, pulmonary embolism, and breast cancer in postmenopausal women

Oral iron supplements (Ferrous sulfate, many vitamin supplements) for life-threatening or fatal reactions in children due to an overdose

Non-steroidal anti-inflammatory drugs (Naproxen, ibuprofen) for cardiovascular events, ulcers, and gastrointestinal bleeding

Combined oral contraceptives (Estrogen and progesterone) for increased cardiovascular risk in smokers, especially in individuals who are older than 35 years

Salicylates (Aspirin) for a severe allergic reaction or Reye syndrome in children

Selective serotonin reuptake inhibitors (Fluoxetine, duloxetine) for increased suicidality in children and adolescents

Some of the boxed warnings and the risk of adverse effects due to use of certain drugs have been publicized by the media since 2004. These include:

Antidepressant medications for an increased risk of suicidal tendencies in children, adolescents, and young adults aged 18-24 years old

Pfizer's non-steroidal anti-inflammatory drug, Celebrex (celecoxib) for cardiovascular and gastrointestinal risks

Depo-Provera's contraceptive injection for the risk of significant loss of bone density that is associated with the long-term use

Warfarin for the risk of bleeding to death

Avandia (rosiglitazone), a drug for diabetes, due to the risk of heart failure or heart attack to patients with an underlying heart disease, or patients who are at a increased risk of a heart attack.

Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin) for the increased risk of ruptures and tendinitis

Chantix (varenicline) due to side effects such as depression, suicidal thoughts, and suicidal actions

Non-steroidal anti-inflammatory drug, Metacam (meloxicam) oral suspension that is approved just for a single post-operative injection in cats

Thyroid hormone stimulating agents for treating obesity due to the increased risk of life-threatening cardiovascular events when high doses are given to hypothyroid populations

Antimalarial drug, mefloquine, for neuropsychiatric and neurological effects

There are several drugs that carry a boxed warning. The aforementioned list doesn't include all the drugs that are required by the FDA to carry a black box warning. The information about these drugs is available on FDA's website and the medication guide created by the manufacturers.

On a concluding note, a black box warning provides critical information that physicians should be aware of. It provides an idea about the potential side effects of a drug, allowing the physician to take prompt steps for tackling such an adverse reaction. Moreover, it provides information related to the importance of dosage or restriction of use of medications. It might mention about those individuals who might be at a higher risk, thereby prompting the physician to consider if the risks outweigh the benefits. Therefore, healthcare professionals must pay heed to these boxed warnings.