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The meaning behind black box and other drug warnings
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Several safety warnings have recently been issued by the FDA that are relevant to antimicrobial agents used in pediatric and adult medicine. What implications do these warnings have for pediatric health care providers? Several specific drug safety warnings will be described in this month’s column, in addition to a discussion about the types of drug warnings issued by the FDA, including black box warnings.
Adverse event reporting system
Reports about potential drug safety concerns are collected in the FDA’s Adverse Event Reporting System (FAERS) database and monitored by safety evaluators and epidemiologists in the FDA’s Office of Surveillance and Epidemiology (OSE). Reports are generated from health care practitioners, the public and mandatory reporting by pharmaceutical manufacturers. Health care practitioners can report potential drug adverse events electronically (www.fda.gov/safety/medwatch/howtoreport/downloadforms).
When sufficient safety data warrant communication to the health care community and public, the FDA will issue a “drug safety communication.” These are described in more detail in this column for several antimicrobials.
Edward A.
Bell
A boxed warning, also commonly known as a black box warning, is issued when reasonable evidence suggests an association of a serious safety hazard with a drug product. A causal relationship does need to be established for a black box warning to appear on a drug’s labeling. A black box warning is issued if use of the drug may result in serious injury or death. Currently, more than 300 commercially available drug products have this type of warning. Several studies describing drugs with black box warnings have been published. The most common type of black box warning describes the use of the drug in specific high-risk patients.
Other black box warnings describe the potential for harm with use of specific doses or because of drug-drug interactions. The most common reason for issuance of a black box warning, or drug withdrawal from the market, for specific drug toxicity is hepatotoxicity.
Specific drug safety communications
The FDA has issued drug safety communications for several antimicrobials this year: ketoconazole, fluoroquinolone antibiotics, mefloquine and azithromycin. A drug safety communication was issued by the FDA in July to highlight concerns on the potential for ketoconazole (given systemically) to result in hepatotoxicity, drug-drug interactions and adrenal gland suppression.
After a review of new safety data, the FDA has required changes to ketoconazole’s labeling, indicating that this triazole antifungal agent should not be used as first-line therapy for any fungal infection. Ketoconazole should no longer be used to treat Candida and dermatophyte infections, unless other antifungal agents are not tolerated. As ketoconazole is a very potent inhibitor of the hepatic cytochrome P450 3A4 isoenzyme, its use with other hepatically metabolized drugs may result in clinically significant drug-drug interactions. As well, ketoconazole’s inhibitory effects on the cytochrome P450 system can also reduce production of endogenous adrenal steroids, resulting in clinically important effects. It is likely that Nizoral (Janssen), a common brand of ketoconazole, will be withdrawn from the market by the manufacturer. Ketoconazole is also available as a generic formulation.
In August, the FDA issued a drug safety communication that described ongoing reports of peripheral neuropathy from systemic use of fluoroquinolone antibiotics (ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin and ofloxacin). Although this adverse effect has been described previously and was added to class product labeling in 2004, the FDA has continued to receive reports of serious peripheral neuropathy. The onset of this adverse effect can be rapid (within days of use) and has been reported to persist for more than 1 year after drug discontinuance. Specific risk factors have not been identified. Thus, the FDA has required changes to fluoroquinolone class labeling (warnings and precautions) to further describe this adverse effect.
A drug safety communication warning was issued in July for mefloquine, an antimalarial agent. A boxed warning was additionally added to mefloquine’s labeling. Before this warning, the labeling included information on contraindications of its use in individuals with pre-existing psychiatric or seizure disorders. This most recent warning describes the possibility of persistent neurologic/vestibular adverse effects, even after drug discontinuance. Some cases have reported permanent vestibular damage, and some psychiatric symptoms have persisted for months or years after drug discontinuance.
These adverse effects have manifested as dizziness, loss of balance, tinnitus, anxiety, depression and hallucinations. Earlier in 2013, the FDA released a drug safety communication for a drug commonly used in pediatrics, azithromycin. This warning related to the potential of azithromycin to result in cardiac QT interval prolongation. Risk factors include those with pre-existing QT interval prolongation, concomitant use other drugs that may also prolong the QT interval, bradycardia, and hypomagnesemia or hypokalemia. Many other drugs may also result in cardiac QT interval prolongation, include other macrolide antibiotics, fluoroquinolone antibiotics, ondansetron, haloperidol, risperidone, selective serotonin reuptake inhibitor (SSRI) antidepressants, trazodone and antiarrhythmics (eg, flecainide). A data set used to support this warning resulted from a large retrospective study published in 2012 of a Medicaid program (cohort of patients aged 30 to 74 years), which revealed a higher risk for cardiovascular death, mostly in individuals with a high baseline risk for cardiovascular death.
Drug safety and the FDA
The FDA serves a primary role to the medical community by ensuring drug product efficacy and safety. Once a new drug is “approved,” or labeled for use in the general public, safety monitoring does not cease, however. As a brief background, newly investigated drugs are evaluated for efficacy and safety in three phases (phase 1, 2, 3). Phase 1 includes administration of the investigative new drug to volunteers without the intended illness to assess safety and dose ranging. Next, in phase 2, the drug is given to larger numbers of individuals with the intended illness to assess drug efficacy, dosing and safety. In phase 3, larger numbers of individuals (eg, several thousand) with the intended illness are given the drug to further evaluate efficacy and safety (often in a blinded, randomized, placebo-controlled manner).
If these cumulative data demonstrate drug efficacy and an acceptable balance between efficacy and safety, the drug is labeled for use by the FDA in a specific population. Once approval and labeling occurs, the new drug product becomes widely available for use. If a new drug may result in rare adverse effects (eg, <1:5,000), these adverse effects would not have likely occurred in phase 1 to 3 studies. Once a new drug is more widely available, such adverse effects may be identified. This may require several years of use and reporting to identify and assess these adverse effects, however. Thus, reporting of drug adverse effects by health care practitioners is vitally important.
The role of the FDA continues past drug approval and labeling. The FDA’s OSE monitors post-approval drug safety (often called phase 4 studies). If important new safety information is identified, the FDA may require changes to the drug label (ie, the package insert), such as in the “warnings and precautions” section; addition of a boxed warning; or it may remove the drug from the market. The FDA may additionally require a risk mitigation strategy for a specific drug product to remain on the market and used in a safer manner. This may entail required drug monitoring or prescriber training, for example.
Health care practitioners and drug safety
There are ways health care practitioners can keep abreast of the most current safety information on drug products and contribute to ensuring ongoing drug safety monitoring. The FDA maintains several websites with the most up-to-date information on drug safety, and health care practitioners can sign up to receive periodic electronic announcements on new drug safety data. The FDA relies on practitioners to report adverse drug events, especially with newly labeled drug products. Health care practitioners need not be certain that a specific drug product did indeed cause an adverse event to report an adverse event with the FDA. Practitioners can report adverse drug events to MedWatch at www.accessdata.fda.gov/scripts/medwatch/.
The author acknowledges and appreciates the assistance and expertise of
FDA. Drug safety communications. Available at: www.fda.gov/Drugs/DrugSafety/ucm199082.htm. Last updated Oct. 11, 2013. Accessed Oct. 21, 2013.
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Edward A. Bell, PharmD, BCPS, is a professor of clinical sciences at Drake University College of Pharmacy, Blank Children’s Hospital, in Des Moines, Iowa. He is also a member of the Infectious Diseases in Children Editorial Board. He can be reached at: Drake University College of Pharmacy, 2507 University Ave., Des Moines, IA 50311; email: ed.bell@drake.edu.
Disclosure: Bell serves on the speakers’ bureau for Sanofi-Pasteur (Sklice) and MedImmune (FluMist Quad).