Pharmacology Watch
Warning Regarding Topical Anesthetics
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In this issue: FDA warning on topical anesthetics; antipsychotics increase sudden cardiac death; the step up vs step down debate; treating pain, fatigue, mood, and sleep in fibromyalgia; FDA Actions.
Something for your pain?
The FDA has issued a warning regarding topical anesthetics and the risk of life-threatening side effects. This is the second warning in 2 years regarding this issue, the first coming in February 2007 following the deaths of two women who used extensive topical anesthetics in preparation for cosmetic procedures. The latest warning was prompted by a study published in Radiology, which compared oral acetaminophen or ibuprofen vs lidocaine gel applied to the skin of the breasts to reduce discomfort during mammography. In the study, 4% lidocaine gel was applied by a nurse from the clavicles to the inferior costal margins and laterally to the mid axillary lines and then covered with plastic wrap to ensure consistency of application. Discomfort from mammograms was significantly lower in the lidocaine gel group and the authors postulate that decreased discomfort may improve the likelihood of future mammographic screening (Lambertz CK, et al. Radiology 2008;248:765-772). The FDA's previous warning in 2007 followed on the heels of two reports of young women undergoing laser hair removal who applied either lidocaine or tetracaine topical preparations to the lower extremities and then covered the application with plastic wrap. Both women developed seizures, fell into a coma, and eventually died due to excessive blood levels of the topical anesthetic. Many of these topical products are available over the counter. The FDA strongly advises consumers not to: make heavy application of topical anesthetics over large areas of skin, use concentrated formulas, apply to broken or irritated skin, wrap the treated skin with plastic wrap or other dressings, or apply heat to skin treated with these products.
Increase in sudden cardiac death
Antipsychotics, both typical and atypical, are associated with a dose-related increase in sudden cardiac death according to a new study. Typical antipsychotics such as thioridazine (Mellaril®) and haloperidol (Haldol®) block repolarizing potassium currents and prolong QT intervals. Multiple studies have shown a dose-related increased risk of sudden cardiac death associated with these drugs. Less is known about the atypical antipsychotic drugs although many have similar cardiovascular effects. Researchers from Nashville reviewed the records of Medicaid enrollees in Tennessee including the records of 44,218 and 46,089 baseline users of a single typical and atypical antipsychotic, respectively. These were matched with 186,600 nonusers of antipsychotic drugs. Thioridazine and haloperidol were the most frequently prescribed typical agents, while clozapine (Clozaril®), quetiapine (Seroquel®), olanzapine (Zyprexa®), and risperidone (Risperdal®) were the most commonly used atypical agents. Both users of typical and atypical antipsychotic drugs had higher rates of sudden cardiac death than nonusers with adjusted incident rate ratios of 1.99 (95% CI, 1.68-2.34) and 2.26 (95% CI, 1.8-2.72), respectively. There was a higher rate for users of atypical antipsychotic drugs vs typical antipsychotics with an incident rate of 1.14 for the comparison (95% CI, 0.93-1.39). For both classes of drugs, the risk for current users increased significantly with increasing dose. The authors conclude that current users of typical and of atypical antipsychotic drugs had similar, dose-related increased risk of sudden cardiac death and that atypical antipsychotic drugs are no safer than the older drugs (Ray WA, et al. N Engl J Med 2009;360:225-235). An accompanying editorial suggests that children and the elderly are particularly vulnerable to these drugs and their use in these populations should be "sharply reduced" (Schneeweiss S, Avorn J. N Engl J Med 2009;360:294-296).
Step up vs step down
Which is more effective for treating dyspepsia: Starting with aggressive therapy and tapering down, or starting with antacids and progressing to more aggressive therapy depending on symptoms? The so called step-up vs step-down debate has raged for years, particularly in managed-care settings. In a new study from the Netherlands, patients with dyspepsia were randomized to treatment with an antacid, H2-receptor antagonist, and proton pump inhibitor (step up) vs the same drugs in reverse order (step down), with each step lasting 4 weeks. Primary outcome was symptom relief and cost-effectiveness of initial management at 6 months. Treatment success after 6 months was achieved in 72% of patients in the step-up group and 70% of patients with step-down group. The average medical costs were lower for patients in the step-up group (€228 vs €245; P = 0.0008) mainly because of the cost of medication. The rate of adverse effects was the same in both groups and were generally mild. The authors suggest that treatment success is similar in both groups but the step-up strategy was more cost-effective for patients with new onset dyspeptic symptoms (van Marrewijk CJ, et al. Lancet 2009;373:215-225). An accompanying editorial suggests that the degree of cost difference between the two groups was overestimated because costs were based on brand name drugs and generics are now available. It furthers suggested that the study may not change practice in primary care as the author recommends a 4-8 week course of a proton pump inhibitor for patients with symptoms of the upper gastrointestinal tract with discontinuation of treatment if patients remain asymptomatic (van Zanten SV. Lancet 2009;373:187-189).
Pain, fatigue, mood, sleep and fibromyalgia
Tricyclics work better than other antidepressants for the treatment of fibromyalgia according to new study from Germany. In a meta-analysis of 18 randomized controlled trials of antidepressants for the treatment of fibromyalgia, researchers reviewed studies utilizing tricyclic and tetracyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAO). All antidepressants were associated with a reduction in pain, fatigue, depressed mood, and sleep disturbances. Pain reduction was particularly good for tricyclic antidepressants, while MAO inhibitors showed modest effect and SSRIs and SNRIs showed a small effect. TCAs were effective in low doses of 12.5-50 mg, far below the doses commonly employed to treat depression, and were very effective for reducing pain, fatigue, and sleep disturbance (JAMA 2009;301:198-209). Currently duloxetine (Cymbalta®), pregablin (Lyrica®), and milnacipran (Savella™) are the only FDA-approved drugs for the treatment of fibromyalgia.
FDA Actions
The FDA is launching a program to improve the safety of imported drugs to the United States. The pilot program would allow manufacturers of drugs outside United States to apply for 1 of 100 certifications, which would require that companies have a secure supply chain for their product. Criteria would include holding an FDA-approved drug application, guaranteeing that active pharmaceutical ingredients would be imported only to make FDA-approved drugs, complying with Good Manufacturing Practices, and guaranteeing that their drug products use a secure supply chain. This program is in response to concerns about manufacturing processes outside the United States and the embargoing of several foreign manufactured drugs in the last year.
This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: [email protected].
FDA warning on topical anesthetics; antipsychotics increase sudden cardiac death; the step up vs step down debate; treating pain, fatigue, mood, and sleep in fibromyalgia; FDA Actions.Subscribe Now for Access
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