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FDA Warning: Pharmaceuticals in "Natural" Products
In this issue: Aspirin dose and cardioprotection; uncovering modafinil's abuse potential; proton-pump inhibitors and clopidogrel; FDA actions.
Finding pharmaceuticals in natural products
Some natural products are not so "natural" after all. The FDA has warned consumers for several months that a number of weight-loss products contain undeclared pharmaceutical ingredients. The newest products to join the list are Herbal Xenicol which contains cetilistat (a drug similar to orlistat that is not approved in this country), as well as Slimbionic and Xsvelten, both of which contain sibutramine (the prescription medication also known as Meridia®). The FDA's list of over-the-counter weight-loss agents that contain undeclared active pharmaceutical ingredients now includes 72 products. Some of the other undeclared pharmaceutical ingredients found in these products include fenproporex (an amphetamine derivative no longer available in this country), fluoxetine (Prozac®, an SSRI), furosemide (Lasix®, a loop diuretic), and even phenytoin (Dilantin®, an antiseizure medication). The FDA is seeking recalls on many of these products; however, some are available only on-line and previous recall efforts have proved inadequate.
In a related story, the FDA has announced a voluntary recall of Zencore Plus, the heavily marketed product for "natural male enhancement," which has been found to contain benzamidenafil, a new PDE5 inhibitor not yet available in this country. Benzamidenafil is similar in action to sildenafil (Viagra®) and tadalafil (Cialis®). PDE5 inhibitors are noted to have a drug interaction with nitrates, leading to potential life-threatening risk of sudden and profound drop in blood pressure. Zencore Plus is distributed by Hi-Tech Pharmaceuticals in Norcross, GA, and is widely sold in health food stores, by mail order, and by Internet sales.
Aspirin dose and cardioprotection
What is the best dose of aspirin for patients taking dual therapy with clopidogrel to prevent cardiovascular events? Investigators looked at 15,595 patients with cardiovascular disease or multiple risk factors in an observational analysis from a double-blind, placebo-controlled randomized trial. Patients were randomized to doses of aspirin less than 100 mg (75 mg or 81 mg), 100 mg, or greater than 100 mg (150 mg or 162 mg) with or without clopidogrel. The primary efficacy outcome was the composite of myocardial infarction, stroke, or cardiovascular death and the primary safety endpoint was severe life-threatening bleeding. In patients given aspirin alone, the hazard ratio for the efficacy and safety endpoints were the same regardless of aspirin dose. In patients given aspirin with clopidogrel, there was a statistically nonsignificant associated reduction in efficacy with aspirin doses over 100 mg, and a significantly higher increase in harm (hazard ratio, 1.30 with clopidogrel plus aspirin greater than 100 mg). The authors conclude that daily doses of aspirin greater than 100 mg were not associated with benefit and may be associated with harm in patients also taking clopidogrel. Therefore, daily doses of aspirin 75-81 mg optimize efficacy and safety in patients requiring long-term aspirin therapy, especially in patients receiving dual antiplatelet therapy (Ann Intern Med 2009;150:379-386). This is especially important given the recent U.S. Preventive Services Task Force recommendation that encourages men ages 45-79 years to take aspirin preventively when the potential benefit of a reduction of myocardial infarction outweighs the potential harm of an increase in gastrointestinal hemorrhage. Women ages 55-79 years are also encouraged to use aspirin when the potential benefit of a reduction in ischemic stroke outweighs the potential harm of increased gastrointestinal hemorrhage (Ann Intern Med 2009;150:396-404).
PPIs and clopidogrel
Increasing evidence suggests that proton pump inhibitors (PPIs) may attenuate the effect of clopidogrel on platelet aggregation. PPIs are often used prophylactically in patients with acute coronary syndrome (ACS), as patients on clopidogrel and aspirin may be at higher risk for GI bleeding. A new study from VA researchers was set up to determine if there are clinical implications from the interaction between PPIs and clopidogrel.
In a retrospective cohort study of 8205 patients with ACS taking clopidogrel, 63.9% were also prescribed a PPI at discharge, during follow-up, or both. Death or rehospitalization for ACS occurred in 20.8% of patients taking clopidogrel without a PPI and 29.8% patients taking clopidogrel with a PPI. Use of clopidogrel plus a PPI was associated with an increased risk of death or rehospitalization for ACS compared with use of clopidogrel without a PPI (adjusted odds ratio, 1.25; 95% confidence interval, 1.11-1.41). Patients taking a combination of the two drugs were at higher risk for hospitalizations for ACS and revascularization procedures, but not for all-cause mortality. Patients taking a PPI without clopidogrel were not at higher risk for rehospitalization. The authors conclude that concomitant use of clopidogrel and a PPI after hospital discharge for ACS is associated with an increase risk of adverse outcomes, suggesting that PPIs may attenuate the benefits of clopidogrel, and that PPIs should only be used with clopidogrel if there is a clear indication, and not for routine prophylaxis (JAMA 2009;301:937-944).
Modafinil's abuse potential
Modafinil (Provigil®) is a wake-promoting medication used to treat narcolepsy and other sleep disorders. Recently, the drug has be used off-label to enhance cognition in psychiatric patients and even in healthy patients seeking a memory boost. Modafinil has been touted as having a low abuse potential; however, a new study questions that assumption. Most stimulant medications, such as methylphenidate and amphetamine, increase brain dopamine levels. Modafinil was thought to exert its effect in the brain on pathways other than dopamine, but now there is evidence that dopamine is involved. Researchers from the National Institute on Drug Abuse looked at 10 healthy male volunteers to measure the effects of modafinil at therapeutic dosing of 200 mg and 400 mg given orally. PET scans were used to measure the effect of modafinil on extracellular dopamine and dopamine transporters. Modafinil increased extracellular dopamine and showed evidence of occupancy of dopamine transporters, effects similar to drugs with the potential for abuse. The authors conclude that, considering the increasing use of modafinil, there needs to be heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations (JAMA 2009;301:1148-1154).
The FDA is requiring the manufacturers of metoclopramide (Reglan®) include a boxed warning on their labeling regarding the risk of long-term or high-dose use and tardive dyskinesia. Manufacturers will also be required to implement a risk evaluation and medication strategy (REMS) to ensure patients are provided with a medication guide that discusses the risk. Metoclopramide is approved for the treatment of gastric motility problems associated with GERD, diabetic gastroparesis, and nausea and vomiting.
A new proton pump inhibitor has been approved by the FDA, bringing the number of PPIs on the market to six. Dexlansoprazole is the purified active isomer of lansoprazole (Pepcid®). The drug has a delayed-release formulation designed to provide two separate releases of the medication. It is approved for the treatment of GERD and erosive esophagitis. Takeda Pharmaceuticals will market dexlansoprazole as Kapidex™.
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, we disclose that 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: firstname.lastname@example.org.