A serious adverse drug event (ADE) is defined as one that causes death, disability, or permanent damage, hospitalization (initial or prolonged), or birth defects.
According to Moore, et al., the number of serious ADEs has increased significantly since 1998 through 2005, according to reports in the Food and Drug Administration (FDA) adverse event reporting system, also known as MedWatch.1 During that time, 467,809 serious ADEs were reported, and the annual number of reports had increased from 34,966 to 89,842.
The number of fatal ADEs increased in that period as well, from 4,419 to 15,109. Further, ADEs related to biotech drugs increased 15.8-fold. The most commonly reported classes with serious ADEs included anti-tumor necrosis factor drugs, interferons, and insulins. Drugs associated with ADEs included some that had been withdrawn from the U.S. market over safety concerns, as well as products that remained on the market.
On Sept. 27, the FDA Amendments Act of 2007 was passed. The measure includes the Prescription Drug User Fee Act (PDUFA), which authorizes the FDA to collect fees from drug makers to supplement funding for the drug-review process.2 A key revision now lets the agency require—not just request—that drug companies perform phase four clinical studies. The PDUFA also includes additional staff for reviewing medical devices. Additional stipulations are that the FDA will:
- Assess signals of serious risk related to drug use as they arise;
- Identify unexpected serious risks;
- Identify when post-marketing studies are needed; and
- Quickly submit a supplement proposing changes to the approved labeling of a drug to reflect new safety information, including changes to boxed warnings, contraindications, warnings, precautions, or adverse reactions within 30 days of identification.
This legislation has brought a number of new warnings on FDA-approved products.
A study in the May 2007 issue of Lancet Infectious Diseases noted higher all-cause mortality in patients treated with cefepime (Maxipime) compared with other beta-lactam antibiotics.3 Cefepime is FDA approved for the treatment of infections caused by susceptible gram-positive and gram-negative micro-organisms. The risk ratio (RR) was 1.26 (95% confidence interval [CI] 1.08–1.49) for cefepime and for the subgroup of patients with febrile neutropenia (RR 1.42 [95% CI 1.09–1.84]). The FDA is reviewing safety data and has requested additional data from Bristol-Myers Squibb to further evaluate the risk of death in cefepime-treated patients. The FDA asks healthcare professionals to report adverse events from cefepime and other agents to MedWatch at www.fda.gov/medwatch/report.htm.
A new warning regarding the pregnancy category and teratogenic effects has been added to the label of mycophenolic acid (MPA) delayed-release tablets (Myfortic). The FDA notes that use of MPA during pregnancy is associated with increased risks of pregnancy loss and congenital malformations, thereby changing the pregnancy category to D (positive evidence of fetal risk) from C (risk of fetal harm cannot be ruled out).
The MPA warnings and precautions sections also have changed. Results from postmarketing data from the U.S. National Transplantation Pregnancy Registry and additional postmarketing data collected in women exposed to systemic mycophenolate mofetil (MMF) during pregnancy brought these revisions. MMF is converted to the active ingredient in MPA following intravenous or oral administration. A patient planning to get pregnant should not use MMF/MPA unless she cannot be treated with other immunosuppressant drugs. Additionally, female patients of childbearing potential must receive contraceptive counseling and use contraception while on this agent. Remember, not only transplant patients receive MMF/MPA; patients with lupus nephritis also use it.