Drug Safety
In July 2012, the U.S. Food and Drug Administration (FDA) issued a draft guidance to manufacturers of over-the-counter (OTC) acetaminophen-containing products, providing different language for the liver warning section of product labelling in an effort to decrease hepatotoxicity.1 The FDA will now allow manufacturers to list the maximum daily dose of 4,000 mg in a 24-hour period, under certain conditions, for this warning. Listing the total milligrams is in lieu of the maximum number of dosage units or capsules, which had been previously required. The new language looks like this “Liver warning: This product contains acetaminophen. Severe liver damage may occur if you take more than 4,000 mg of acetaminophen in 24 hours, or you take it with other drugs containing acetaminophen, or with three or more alcoholic drinks daily while you are using this product.” All OTC acetaminophen-containing products must contain a warning that using more than 4,000 mg of acetaminophen has been associated with severe liver damage. The warning has been changed from the maximum number of dosage units to the actual dosage, to avoid confusion.
Data continue to amass on atypical femoral fractures in patients using bisphosphonates for osteoporosis prevention and treatment.2 Meier et al published a case-control multivariate logistic regression to assess the association of bisphosphonate use and atypical femoral fracture, and the incidence rates of each fracture type. A total of 477 patients aged 50 years and older, hospitalized with a subtrochanteric or femoral shaft fracture, were evaluated. The occurrence of current or prior bisphosphonate treatment with alendronate, risedronate, pamidronate, ibandronate, etidronate, or zoledronic acid was also evaluated utilizing a detailed medication review of hospital computerized medical records at one institution between 1999 and 2010. Patient admission radiographs and complete medical records were scrutinized. Patients were classified as having either an atypical or classic femoral fracture, and they were compared to a random sample of 200 healthy individuals without femoral fractures. Thirty-nine patients with atypical fractures and 438 patients with classic fractures were identified. Although the absolute fracture number was very small, 82% of patients with atypical fractures (n=32) had been treated with bisphosphonates compared with 6% (n=28) of patients within the classic fractures group, and 12% in the group without fractures. Atypical femoral fractures increased over a 12-year period.
Zhang et al retrospectively analyzed more than 400,000 Medicare recipient claims from 2006 to 2009, including 18,683 patients aged 60 years and older who were vaccinated for Herpes Zoster.3 All patients had been diagnosed with immune-mediated diseases including rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease. All patients had been treated with either antitumor necrosis factor (TNF) biologics, non-TNF biologics (e.g., abatacept, rituximab), nonbiologic disease-modifying antirheumatic drugs (DMARDs), and/or oral corticosteroids. The investigators evaluated associations between receiving the vaccine and development of herpes zoster within the first 42 days following vaccination, and in the following 3.5 years (median follow-up, 2.0 years). No herpes zoster cases occurred in the individuals who received the vaccine (n=633) and who were also exposed to biologics at the vaccination time or within the next 42 days. Of 7,780 people who received the herpes zoster vaccination, fewer than 11 cases of herpes zoster occurred within 42 days of being vaccinated, resulting in an overall incidence of 7.8 cases per 1,000 person-years. There was also a lower herpes zoster rate during the follow-up period in vaccinated individuals. The herpes zoster rate was 11.6 cases per 1,000 person-years in unvaccinated individuals. These study results showed that being vaccinated against herpes zoster did not increase the short-term varicella risk in people with immune-mediated diseases, including those who received biologics (e.g., anti–TNF-α agents).
The FDA has approved a risk mitigation and evaluation strategy (REMS) for more than 20 manufacturers of extended-release/long-acting opioids for chronic pain management.4 Under the new REMS, these manufacturers are required to make education programs available to prescribers based on an FDA blueprint. It is expected that this will happen through educational grants for continuing medical education programs, with topics such as weighing opioid risks and benefits; appropriately choosing patients for opioids; monitoring and managing patients; counseling patients on the safe use of long-acting opioids; how to recognize evidence of and the potential for opioid misuse, abuse, and addiction; and both specific and general opioid drug information. It is anticipated that these activities will begin by March 1, 2013. Patient education is also a component of the new REMS. Patient counseling information has been updated with consumer-friendly information on the safe use, storage, and disposal of these agents, as well as other useful patient information, such as how to prevent accidental exposure.
The FDA Watch List
The FDA has added 16 drugs to its quarterly Watch List of agents identified in the last quarter of 2011.5 These agents have potential signs of serious risks or new safety information, identified through the Adverse Event Reporting System (AERS). The FDA continues to monitor these agents to determine if a causal link exists. If a causal link is established, the FDA will then consider a regulatory response such as assembling more information to better differentiate the risk, updating the medication label (e.g., package insert) or requiring a REMS. Some of the identified agents and their potential reactions include: fluoroquinolones and peripheral sensorimotor neuropathy; gabapentin and increases in blood creatinine phosphokinase levels and rhabdomyolysis; milnacipran and homicidal ideation; and pegloticase and anaphylaxis/infusion reactions.
In the Watch List from the third quarter of 2011, eight drugs were identified, five of which underwent label changes. Two of these agents were adalimumab and golimumab. Both received updated warnings and precautions sections of their labeling, related to the development of optic neuritis.
Drug Approvals/Modifications
On January 13, 2011, the FDA asked pharmaceutical manufacturers to limit the strength of acetaminophen in prescription-drug products to 325 mg per dosage form in order to make them safer for patients.6 The deadline for complying with this new limit is January 14, 2014. Abbott Pharmaceuticals has decided to comply in advance, and will be relaunching its combination hydrocodone bitartrate/acetaminophen products (Vicodin) with 300 mg of acetaminophen beginning in the third quarter of this year.7 The amount of hydrocodone bitartrate will remain the same as in prior formulations (e.g., Vicodin plain, ES, and HP), but all will contain 300 mg of acetaminophen. Patients who use acetaminophen for pain relief should regularly be informed that hepatotoxicity risk increases when different products which contain acetaminophen are taken at one time, and that exceeding 4,000 mg in a 24-hour period is not recommended.
The combination of phentermine and topiramate has been FDA approved for overweight or obese patients who have at least one weight-related condition, including hypertension, diabetes, or dyslipidemia.8 This combination product, known as Qysmia, is approved with a REMS. It is the second weight-loss product to be approved in more than ten years.
Lorcaserin was FDA approved in late June as an adjunct to a reduced-calorie diet and exercise for chronic weight management in obese (body mass index [BMI]>30) or overweight (BMI>27) adults with at least one of the weight-related conditions noted above.9 Lorcaserin activates the serotonin 2C receptor in the brain, which may help patients eat less and feel sated after eating smaller food amounts. Lorcaserin can cause serotonin syndrome if used with other medications that increase serotonin levels or activate serotonin receptors. These agents include migraine therapies and antidepressants. Lorcaserin can also cause memory and attention disturbances. Both Lorcaserin and Qysmia can cause headaches, nausea, dizziness, and fatigue, and the FDA is requiring that the manufacturers of both agents conduct longer-term studies to evaluate stroke and heart risks.10
Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.
References
- U.S. Food and Drug Administration. Organ-specific warnings: Internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use—Labeling for products that contain acetaminophen. Published July 2012. Available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM310477.pdf. Accessed August 7, 2012.
- Meier RPH, Perneger TV, Stern R, Rizzoli R, Pete RE. Increasing occurrence of atypical femoral fractures associated with bisphosphonate use. Arch Intern Med. 2012;172:930-936.
- Zhang J, Xie F, Delzell E, et al. Association between vaccination for herpes zoster and risk of herpes zoster infection among older patients with selected immune-mediated diseases. JAMA. 2012;308:43-49.
- Liscinsky M. FDA introduces new safety measures for extended-release and long-acting opioid medications. Published July 9, 2012. Available at www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm310870.htm. Accessed July 19, 2012.
- Lowes R. FDA puts 16 drugs on watch list. Published April 17, 2012. Available at www.medscape.com/viewarticle/762205. Accessed July 17, 2012.
- FDA Drug Safety Communication. Prescription acetaminophen products to be limited to 325 mg per dosage unit; boxed warning will highlight potential for severe liver failure. Published January 13, 2011. Available at www.fda.gov/Drugs/DrugSafety/ucm239821.htm. Accessed August 7, 2012.
- Abbott Pharmaceuticals. Vicodin: Health professionals FAQs. Published May 2012. Available at www.vicodin.com/hcp/faq.cfm. Accessed August 7, 2012.
- Dane L. FDA approves Vivus’ weight loss drug Qsymia. Published July 12, 2012. Available at www.firstwordpharma.com/node/1002971. Accessed July 19, 2012.
- U.S. Food and Drug Administration. FDA approves Belviq to treat some overweight or obese adults. Published June 27, 2012. Available at www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm309993.htm. Accessed August 7, 2012.
- Kotz D. Should you take one of the new weight loss drugs? Published July 19, 2012. Available at www.boston.com/dailydose/2012/07/19/should-you-take-one-the-new-weight-loss-drugs/BwVXJevZ7FutoFttOQiKlM/story.html. Accessed July 20, 2012.
