(To report drug-related problems: [telephone] 1-800-332-1088; [fax] 1-800-332-0178; http://www.fda.gov/medwatch . Provide information for differential diagnosis and assessment of cause, time course of the reaction, and normal ranges of laboratory tests.):
Use the hyperlink below to see the FDA video on this important subject. (Copy and drop into your browser)
http://www.connectlive.com/events/fdatv/fda-show49-seg3-150k.asx
[Posted 05/12/2006] GlaxoSmithKline (GSK) and FDA notified healthcare
professionals of changes to the Clinical Worsening and Suicide Risk
subsection of the WARNINGS section in the prescribing Information for Paxil
and Paxil CR. These labeling changes relate to adult patients, particularly
those who are younger adults.
A recent meta-analysis conducted of suicidal behavior and ideation in
placebo-controlled clinical trials of paroxetine in adult patients with
psychiatric disorders including Major Depressive Disorder (MDD), other
depression and non-depression disorders. Results of this analysis showed a
higher frequency of suicidal behavior in young adults treated with
paroxetine compared with placebo. Further, in the analysis of adults with
MDD (all ages), the frequency of suicidal behavior was higher in patients
treated with paroxetine compared with placebo. This difference was
statistically significant; however, as the absolute number and incidence of
events are small, these data should be interpreted with caution. All of the
reported events of suicidal behavior in the adult patients with MDD were
non-fatal suicide attempts, and the majority of these attempts (8 of 11)
were in younger adults aged 18-30. These MDD data suggest that the higher
frequency observed in the younger adult population across psychiatric
disorders may extend beyond the age of 24.
It is important that all patients, especially young adults and those who are
improving, receive careful monitoring during paroxetine therapy regardless
of the condition being treated.
Additionally, new warnings have been added to the labeling for Paxil and generic paroxetine
based on preliminary analyses of two recent unpublished epidemiologic studies.
Both studies showed a relatively small increased risk for cardiac defects in
infants born to women who received the drug in early pregnancy, and one study
also showed an increased risk of congenital malformations overall.
In both studies, the most common types of cardiac abnormalities in children of
women who took Paxil were atrial and ventricular septal defects, with a wide
range of severity. Neither of the studies addressed the question of whether the
risk might extend to use of the drug later in pregnancy.
FDA is recommends that Paxil generally not be started in women who are planning
to become pregnant, or are in the first trimester of pregnancy. If a woman is
already on Paxil, the physician should alert her about the potential risk to the
fetus. The physician should also consider discontinuing the drug in these women,
although in individual cases the benefits of continuing Paxil may outweigh the
potential risk to the fetus. If Paxil is discontinued, it should be tapered off
and not stopped suddenly.
* * *
Drug Interactions: CITALOPRAM (Celexa)
Following a review of the data from the medical literature as well as data from our global post-marketing safety database, the FDA and Novartis have determined that the conconmitant use of Clozaril and citalopram results in clinically significant elevations of Clozaril blood concentrations. Consequently, the PRECAUTIONS (Pharmacokinetic- Related Interactions) section of the PI was revised to include citalopram.
ALSO: From the New England Journal of Medicine, February 16, 2006
Drug-Related Hepatotoxicity
Victor J. Navarro, M.D., and John R. Senior, M.D.
In this review, we define hepatotoxicity as injury to the liver that is associated with impaired liver function caused by exposure to a drug or another noninfectious agent. The distinction between injury and function is important, because it is mainly when function is impaired that symptoms and clinically significant disease follow. We are especially concerned with serious drug-related hepatotoxicity that is disabling or life-threatening or that requires hospitalization. Although drug-related hepatotoxicity is uncommon — for many drugs, the reported incidence is between 1 in 10,000 and 1 in 100,000 patients — its true incidence is difficult to determine. The numbers may be much higher, because of underreporting, difficulties in detection or diagnosis, and incomplete observation of persons exposed. In an effort to improve on the reporting of rates, a group of physicians in France were trained to investigate and report possible causes of hepatic injury from drugs and found a crude incidence rate of about 14 per 100,000 inhabitants per year, 12 percent of whom were hospitalized and 6 percent of whom died. This rate was about 16 times as great as the spontaneously reported rates of adverse hepatic drug reactions in France but was still a possible underestimate.
In most cases, there is no effective treatment other than stopping the drug and providing general supportive care. Prompt use of N-acetylcysteine after acetaminophen overdose and intravenous carnitine for valproate-induced mitochondrial injury are exceptions. In the United States, drug-related hepatotoxicity is now the leading cause of acute liver failure among patients referred for liver transplantation — most of whom have had no prior liver disease — because of an intentional or unintentional overdose of acetaminophen, the drug most often implicated in such cases. When a drug is found to cause even rare hepatotoxicity but is used by millions, it may be removed from clinical use. Although such a drug poses great danger to only a few patients, its removal leads to the loss of drug availability to many. For practicing physicians, drug-related hepatotoxicity is a liability risk; for the pharmaceutical industry, it leads to financial losses; and from a regulatory perspective, it is the most common reason for regulatory actions on the part of the Food and Drug Administration (FDA).
Given its rarity, drug-related hepatotoxicity may not occur during clinical trials, which are usually limited to a few thousand participants. However, after approval of a drug for use and subsequent marketing, large numbers of patients are exposed, and rare toxic effects may emerge. In this article we provide information on the detection, evaluation, possible prevention, and management of drug-related hepatotoxicity. Although our discussion focuses primarily on hepatotoxicity associated with prescribed and over-the-counter medications, the same principles apply to other agents, including dietary supplements and complementary or alternative remedies.
Liver Injury and Its Patterns
In 1989, a panel of 12 European and American experts by consensus defined liver injury as an increase of more than twice the upper limit of the normal range in the levels of serum alanine aminotransferase or conjugated bilirubin, or a combined increase in the levels of aspartate aminotransferase, alkaline phosphatase, and total bilirubin, provided that one of these was more than twice the upper limit of the normal range. The clinical patterns of liver injury were further characterized as hepatocellular, with a predominant initial elevation of the alanine aminotransferase level, or cholestatic, in which the serum alkaline phosphatase level is first elevated. These patterns of liver injury are not mutually exclusive and may be termed mixed if intermediate. It was later suggested, before a February 2001 conference cosponsored by the FDA Center for Drug Evaluation and Research, the Pharmaceutical Research and Manufacturers of America, and the American Association for the Study of Liver Diseases, that an alanine aminotransferase level of more than three times the upper limit of normal and a total bilirubin level of more than twice the upper limit be used as a combined test to define clinically significant abnormalities on liver tests, with further verification through the analysis of additional clinical data. Elevations in serum enzyme levels (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) were taken as indicators of liver injury, whereas increases in both total and conjugated bilirubin levels were measures of overall liver function. It is important to recognize the pattern of liver injury, since certain drugs tend to create injury predominantly according to one pattern or the other .
True measures of conjugated bilirubin are seldom obtained, and the direct-reacting bilirubin fraction is an overestimate. The concept of combining the measures of liver injury and function was derived from the observation of the late Hyman Zimmerman that "drug-induced hepatocellular jaundice is a serious lesion. The mortality rate ranges from 10 to 50 percent." This observation, referred to by Dr. Robert Temple as "Hy's Law," has shown notable consistency, and it continues to be used by the FDA to initiate close evaluation of patients with elevated liver tests. Two recent surveys, from Sweden and Spain, provide support for the observation that drug-induced hepatocellular injury with jaundice is associated with greater mortality or the need for transplantation than is cholestatic or mixed injury. However, in each case, additional clinical information is required to determine whether the elevated values were drug-induced or disease-induced.
Injury vs. Function
Liver injury is generally indicated by elevations in serum aminotransferase levels, but increases of far more than three times the upper limit of normal may not lead to clinically significant liver damage. This is because of the great capacity of the liver to heal injury, with the subsequent development of adaptive tolerance, as frequently seen with initial exposure to drugs such as isoniazid and tacrine. Tests reflecting liver injury alone do not necessarily predict or indicate serious hepatotoxicity. Vague symptoms such as fatigue, anorexia, nausea, discomfort in the right upper quadrant, and dark urine may be the first clues that hepatotoxicity has occurred. Drug-related hepatotoxicity should be considered when such symptoms occur in conjunction with biochemical evidence of liver injury, and especially with concurrent impaired liver function. The regulation of serum enzyme activity is not a function of the liver, which is more accurately assessed according to the levels of total bilirubin or conjugated bilirubin — reflecting the liver's ability to move bilirubin from plasma into bile. Another measurable liver function is protein synthesis, which is reflected in the albumin concentration and the prothrombin time (or its international normalized ratio [INR]).
Clinical Patterns of Hepatotoxicity
Hepatotoxicity may be predictable or unpredictable. Predictable reactions typically are dose-related and occur in most persons who are exposed shortly after some threshold for toxicity is reached. Acetaminophen is a fairly predictable hepatotoxin, as are chemicals such as carbon tetrachloride, phosphorus, and chloroform that are no longer used as drugs. Unpredictable hepatotoxic reactions occur without warning, are unrelated to dose, and have variable latency periods, ranging from a few days to 12 months. Many drugs create a pattern of injury that has characteristic biochemical, clinical, histologic, and chronologic features, or a combination of them. Together, these features form what is termed a drug's signature disease.
Several patterns of drug-related hepatotoxicity may be recognized, each with a different mechanism of injury. Hepatocellular or cytolytic injury involves marked elevations of serum aminotransferase levels, usually preceding increases in total bilirubin levels and modest increases in alkaline phosphatase levels; examples of this type of injury include that attributable to isoniazid or troglitazone. Cholestatic injury is characterized by increases in alkaline phosphatase levels that precede or are relatively more prominent than increases in the alanine aminotransferase or aspartate aminotransferase levels and is associated with amoxicillin–clavulanic acid or chlorpromazine. Hypersensitivity or immunologic injury is often somewhat delayed or occurs on repeated exposure after an interval, perhaps with associated fever, rash, or eosinophilia. It is often more rapid and more severe on repeated exposure (and dangerous on "rechallenge"), as exemplified by injury associated with phenytoin, nitrofurantoin, or halothane. This has been referred to as a drug-hypersensitivity syndrome. Mitochondrial injury involves microvesicular steatosis on liver biopsy, lactic acidosis, and modest elevations of aminotransferase levels and may be caused by valproic acid or high-dose parenteral tetracycline.
Mechanisms of Hepatotoxicity and Susceptibility Factors
Drug-related hepatotoxicity cannot be viewed as a single disease. Many different mechanisms lead to hepatotoxicity, including disruption of the cell membrane and cell death resulting from covalent binding of the drug to cell proteins, which creates new adducts that serve as immune targets, thus inciting an immunologic reaction; inhibition of cellular pathways of drug metabolism; abnormal bile flow resulting from disruption of subcellular actin filaments or interruption of transport pumps, leading to cholestasis and jaundice, sometimes with minimal cell injury; programmed cell death (apoptosis), occurring through tumor-necrosis-factor and Fas pathways; and inhibition of mitochondrial function, with accumulation of reactive oxygen species and lipid peroxidation, fat accumulation, and cell death. More detailed discussions of these and other mechanisms have been presented by Lee and by Kaplowitz.
Adults are generally more susceptible to hepatotoxicity than are children, and women are more commonly affected than men. Obesity and malnutrition — particularly in the case of acetaminophen, which, when used in patients with malnutrition, may deplete glutathione — are susceptibility factors. Death attributable to the ingestion of acetaminophen is usually associated with doses of 15 to 25 g; some evidence suggests that alcohol use and fasting lower the threshold for hepatotoxicity from acetaminophen. Pregnancy, concomitantly administered medications, and a history of drug reactions also increase susceptibility. Preexisting liver disease and coexisting illnesses may have a greater effect on the ability of the patient to recover from liver injury than on the likelihood that it will develop.
Possibly the most important susceptibility factor for hepatotoxicity is genetic variability. Genetic polymorphisms have a strong influence on drug metabolism and may increase risk. For example, polymorphism of the N-acetyltransferase 2 gene differentiates fast from slow acetylators; the latter have increased susceptibility to isoniazid toxicity. The recent linkage of irinotecan toxicity to a diminished capacity for glucuronidation in patients with Gilbert syndrome is another example:
Approximately 1.8 percent of the U.S. population carries antibodies to the hepatitis C virus; 74 percent have viremia and are at risk for chronic liver disease. Nonalcoholic fatty liver disease is even more common. Patients with hyperlipidemia frequently have elevations in aminotransferase levels due to nonalcoholic fatty liver disease; such patients do not appear to be at increased risk for statin-associated hepatotoxicity.
Diagnosis
The appearance of symptoms ranging from nonspecific anorexia, nausea, and fatigue to obvious jaundice in the setting of the use of prescription or nonprescription medication or dietary supplements should raise the suspicion of drug-related hepatotoxicity. Other causes of liver injury must be ruled out, including hepatitis A or B infection (and, less often, acute hepatitis C infection), alcoholic or autoimmune hepatitis, biliary tract disorders, and hemodynamic problems. Viral hepatitis can be evaluated by measuring hepatitis A IgM antibody, hepatitis B surface antigen, and hepatitis C antibody or hepatitis C RNA, which are positive in acute hepatitis A, B, and C, respectively. In developing countries, liver injury may result from hepatitis E infection, in which case the presence of antibody should be determined. Biliary abnormalities may lead to liver injury through obstruction or infection, as occurs in cholecystitis or cholangitis. Imaging of the biliary tree, with ultrasonography followed by cross-sectional imaging with computed tomographic scanning or magnetic resonance imaging, is appropriate. The use of endoscopic retrograde cholangiopancreatography allows for the coupling of diagnosis with interventions to relieve obstruction.
Liver injury attributable to alcohol should be suspected if there is
a history of recent consumption, a detectable serum alcohol level, or
an aspartate aminotransferase level greater than that of alanine
aminotransferase by a ratio of 2:1. Autoimmune disease should be
suspected if liver injury occurs in the presence of antinuclear or
smooth-muscle antibodies or of elevated globulin levels. Hemodynamic
abnormalities, such as cardiovascular shock or heart failure, may
cause liver injury. In this situation, a history of hypotension or
syncope is common. Finally, genetic and metabolic disorders may
produce liver injury: elevations in ferritin and iron levels and in
total iron-binding capacity may suggest the presence of
hemochromatosis; a low alpha1-antitrypsin level and an
abnormal phenotype may suggest disease associated with a deficiency
of this protein; and a low ceruloplasmin level in a young person with
liver injury suggests the possibility of Wilson's disease. Liver
injury in the absence of another cause may be drug-related but
requires additional information, such as that obtained through a
careful drug history, in relation to the onset of injury.
Serum-chemistry tests must be supplemented by additional clinical evidence to determine accurately whether the injury has been caused by disease or a drug. Various methods have focused on scoring factors, including the timing of exposure, age, alcohol use, pregnancy, the concomitant use of medications, the exclusion of nondrug causes, known information about drug reactions, and the response to rechallenge. Each factor is given points, which, when summed, allow the clinician to diagnose hepatotoxicity with varying levels of confidence.
The clinical presentations of hepatotoxicity that are most readily distinguished are acute hepatocellular injury and cholestatic liver disease. Acute hepatocellular injury often is associated with symptoms of malaise, abdominal pain, and jaundice. The alanine aminotransferase level is markedly elevated, with minimal elevations in the alkaline phosphatase level. The combination of jaundice, impaired hepatic function (indicated by an increased prothrombin time or its INR), and encephalopathy indicates particularly severe liver injury. The development of these signs less than 26 weeks after the onset of illness in a patient without preexisting cirrhosis is the hallmark of acute liver failure. This syndrome has a poor prognosis without liver transplantation and is a problem of great concern.
Cholestatic liver disease is characterized by jaundice and pruritus, with the alkaline phosphatase level being the most prominently elevated of the liver-enzyme levels initially. Recovery is usually complete but may take several weeks or months. In rare cases, chronic liver injury may occur owing to a self-perpetuating injury termed the vanishing bile duct syndrome. Cholestatic drug-induced hepatotoxicity is less likely to be immediately serious but may be prolonged.
Management
In the presence of symptoms, particularly jaundice, and of impaired hepatic function or clinical signs of acute liver failure (e.g., encephalopathy), the use of any agent suspected of causing hepatotoxicity should be stopped. Liver injury should be assessed biochemically, immediately and serially, with prompt consultation from a hepatologist or gastroenterologist. Rechallenge usually should not be performed, since a recurrent injury may be more severe than the initial insult, especially if the injury is immunologic.
Improvement occurs in most cases, although at variable rates, and is not always immediate after the offending drug is stopped. In fact, liver injury may worsen or follow a protracted course of recovery over weeks or months. Not infrequently, drugs cause transient and asymptomatic but not progressive elevations of aminotransferase levels even while the exposure to a drug continues, and this may represent adaptation. Statins have been shown to cause elevations of aminotransferase levels and severe liver injury in animals; in humans such elevations are common but rarely, if ever, lead to clinically significant hepatotoxicity. Isoniazid is another example of a drug that commonly causes elevations of liver enzyme levels, yet such increases require permanent cessation of the administration of the drug in only about 1 in 1000 patients.
Prevention
The Drug-Development Process
The first opportunity to prevent hepatotoxicity arises in the early stages of drug development, when animals are exposed to a drug and assessments with regard to toxicity are made. Preclinical studies in animals are more useful for detecting dose-related, predictable hepatotoxicity than they are for detecting unpredictable hepatotoxicity in humans. Phase 1 safety studies provide the first opportunity to identify drug-related hepatotoxicity in humans. These studies are limited by their small number of participants — 12 to 30 healthy subjects — and the brief exposure of these subjects to low doses of a given drug. During efficacy testing, more patients are exposed to a drug, and the likelihood that hepatotoxicity will become evident is higher; however, the limited number of participants involved in controlled clinical trials means that a 95 percent or greater chance of even one case of a rare event occurring with a true incidence of 1 in 1000 subjects requires that almost 3000 be observed.
The case of troglitazone highlights the importance of recognizing signs of hepatotoxicity during drug development. Troglitazone (Rezulin) was the first peroxisome-proliferator–activated receptor agonist approved for use in achieving blood glucose control in patients with non-insulin-dependent diabetes. During clinical trials, 12 of 2510 patients treated with troglitazone had alanine aminotransferase levels of more than 10 times the upper limit of the normal range, and 5 had levels of more than 20 times the upper limit of normal; biopsies were performed in 2 patients, including 1 in whom jaundice developed. These observations proved to be predictive of adverse events after troglitazone was marketed, when liver failure developed in 94 of the nearly 2 million patients who used the drug. Ultimately, troglitazone was withdrawn from the market, in March of 2000. This situation highlighted the need to appreciate signals that predict hepatotoxicity while a drug is being developed.
Post-Marketing Surveillance
Currently, the period after a drug is approved is the most important for identifying hepatotoxicity. At present, the FDA's MedWatch program is a good way to report suspected drug-related hepatotoxicity. This voluntary reporting system is limited in the use and adequacy of reported clinical details. Case reports that appear in the literature also draw attention to potential hepatotoxins, particularly substances that are not studied by the manufacturer or regulated by the FDA, such as herbal and over-the-counter complementary and alternative medications.
Monitoring of Liver Tests in Clinical Practice
There is no evidence to show that, despite instructions and warnings on drug labels, routine monitoring of liver enzymes prevents clinically significant hepatotoxicity, most of which is unpredictable and quite uncommon. Thus, an argument can be made that a more effective and efficient method of detecting and preventing hepatotoxicity would involve vigilance on the part of the patients themselves in recognizing symptoms, followed by prompt medical evaluation. Admittedly, such an approach may not apply to all drugs.
Pharmacogenomics
Exploitation of the growing body of knowledge of genetic polymorphisms, through the field of pharmacogenomics, should revolutionize our ability to prevent hepatotoxicity. The emerging fields of proteomics and metabonomics also promise insights into the mechanisms of drug-related hepatotoxicity.
It has been postulated that tailoring drug therapy to individual patients may maximize therapeutic effects while minimizing hepatotoxicity, but as yet no genetic tests have come into routine clinical use.
Clinical Research
Only large prospective trials can provide missing information on drug-related hepatotoxicity, such as its true incidence and associated risk factors, and allow access to biologic samples to learn more about its mechanisms. The multicenter Acute Liver Failure Study collects information on cases of acute liver failure at 50 liver-transplantation centers across the United States. This ongoing study has made several important contributions to the understanding of hepatotoxicity, including the finding that drugs are the most frequent cause of acute liver failure. The National Institutes of Health has funded a multicenter network of five institutions aimed at studying drug-induced liver injury. In an attempt to better understand the metabolic pathways involved in hepatotoxicity, this study will facilitate pharmacogenomic exploration through the development of a specimen bank of DNA samples from patients who have idiosyncratic drug reactions.
Dr. Navarro reports having received consulting fees from Merck Research Laboratories as a member of a safety monitoring committee, lecture fees from Axcan Pharma and Astellas Pharma, and research support from Roche Pharmaceuticals. He has provided expert opinion in legal cases involving hepatotoxicity and troglitazone and serves as a drug-safety consultant for One World Health, a nonprofit pharmaceutical company. No other potential conflict of interest relevant to this article was reported.
Dr. Senior is an employee of the FDA and has no conflicts to report. However, the views expressed in this article represent the opinions of the authors and do not reflect an official position statement of either Jefferson Medical College or the FDA.
We are indebted to Drs. Paul Watkins, Anthony DiMarino, and Paul Seligman for their critical review of the manuscript, and to Dr. Raphael Rubin for histologic examples of various liver injuries.
Source Information
From the Department of Medicine, Division of Gastroenterology and Hepatology, Jefferson Medical College, Philadelphia (V.J.N.); and the Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Md. (J.R.S.).
From the New England Journal of Medicine, February 9, 2006
Selective Serotonin-Reuptake Inhibitors and Risk of Persistent Pulmonary Hypertension of the Newborn
Christina D. Chambers, Ph.D., M.P.H., Sonia Hernandez-Diaz, M.D., Dr.P.H., Linda J. Van Marter, M.D., M.P.H., Martha M. Werler, Sc.D., Carol Louik, Sc.D., Kenneth Lyons Jones, M.D., and Allen A. Mitchell, M.D.
ABSTRACT
Background Persistent pulmonary hypertension of the newborn (PPHN) is associated with substantial infant mortality and morbidity. A previous cohort study suggested a possible association between maternal use of the selective serotonin-reuptake inhibitor (SSRI) fluoxetine late in the third trimester of pregnancy and the risk of PPHN in the infant. We performed a case–control study to assess whether PPHN is associated with exposure to SSRIs during late pregnancy.
Methods Between 1998 and 2003, we enrolled 377 women whose infants had PPHN and 836 matched control women and their infants. Maternal interviews were conducted by nurses, who were blinded to the study hypothesis, regarding medication use in pregnancy and potential confounders, including demographic variables and health history.
Results Fourteen infants with PPHN had been exposed to an SSRI after the completion of the 20th week of gestation, as compared with six control infants (adjusted odds ratio, 6.1; 95 percent confidence interval, 2.2 to 16.8). In contrast, neither the use of SSRIs before the 20th week of gestation nor the use of non-SSRI antidepressant drugs at any time during pregnancy was associated with an increased risk of PPHN.
Conclusions These data support an association between the maternal use of SSRIs in late pregnancy and PPHN in the offspring; further study of this association is warranted. These findings should be taken into account in decisions as to whether to continue the use of SSRIs during pregnancy.
* * *
Washington Post February 8:
Low-Fat Diet's Benefits
Rejected
Study Finds No Drop In Risk for Disease
By Rob Stein
Washington Post Staff Writer
Wednesday, February 8, 2006; A01
Low-fat diets do not protect women against heart attacks, strokes, breast cancer or colon cancer, a major study has found, contradicting what had once been promoted as one of the cornerstones of a healthy lifestyle.
The eight-year study of nearly 50,000 middle-age and elderly women -- by far the largest, most definitive test of cutting fat from the diet -- did not find any clear evidence that doing so reduced their risks, undermining more than a decade of advice from many doctors.
The findings run contrary to the belief that eating less fat would have myriad health benefits, which had prompted health authorities to begin prominent campaigns to get people to eat less fat and the food industry to line grocery shelves with low-fat cookies, chips and other products.
"Based on our findings, we cannot recommend that most women should follow a low-fat diet," said Jacques Rossouw of the National Heart, Lung and Blood Institute, which funded the $415 million study.
Although the study involved only women, the findings probably apply to men as well, he said.
Several experts cautioned, however, that the study hints that there still may be some benefits to reducing the total amount of fat in the diet, especially for breast cancer. In addition, there is clear evidence from this and other studies that particular fats -- saturated fats from meat and trans fats from processed foods -- are unhealthful and should be avoided.
But the findings, being published today in three papers in the Journal of the American Medical Association, deflate the notion that a simple, easily communicated message of reducing overall fat intake would stave off a host of ills.
"We set out to test a promising but unproven hypothesis that has proven to be less promising than we anticipated," Rossouw said. "This is the nature of science: to have incremental gains and setbacks. We have a duty as scientists to put the best information out there at any given time, even if it can become confusing at times."
Skeptics said the findings confirm their long objections to the message that all fat is bad. That strategy may have diverted attention from much more effective approaches that differentiate between healthful and detrimental fats and may have contributed to the obesity epidemic because people worried more about how much fat they ate than how many calories they consumed, they said.
"It was a mistake, and this study really confirms that it was the wrong direction to go for nutritional advice," said Walter Willett of the Harvard School of Public Health. "It did do harm. It was a lost opportunity. People were given the idea that it was only fat calories that counted. This should be the nail in the coffin for low-fat diets."
Willett and other researchers fear that the findings will leave the public skeptical about all health advice, or will be misinterpreted to mean that diet and lifestyle are unimportant. A large and convincing body of evidence shows that eating a diet rich in fruits, vegetables and whole grains and low in saturated and trans fats; avoiding smoking; exercising regularly; and maintaining an appropriate weight have a powerful effect on health, they said.
"There's a danger people will throw up their hands and say, 'Why should I believe anything else?' " Willett said. "But there is strong evidence that diet and lifestyle do make a big difference."
The findings stem from the Women's Health Initiative, which also shocked the medical establishment in 2002 when it showed that taking hormones not only did not protect the hearts of postmenopausal women but also was dangerous.
For the new findings, researchers analyzed data from 48,835 women age 50 to 79 who joined the study between 1993 and 1998. About 40 percent were counseled to eat more fruits and vegetables and to cut their overall fat intake, with the goal of reducing their total fat consumption to no more than 20 percent of their daily calories.
After about eight years, those women had cut their total fat from 35 to 38 percent to 24 to 29 percent on average, while the rest continued to consume about the same amount.
The women on the low-fat diet had slightly lower levels of "bad" cholesterol -- low-density lipoprotein -- and blood pressure, but their risk of heart attack, stroke and heart disease was unaffected, one paper showed. There were indications, however, that women who cut down on saturated fat, or who ate more fruits and vegetables, did lower their risk.
Similarly, when the researchers looked at colorectal cancer, the women who cut their fat intake had no decrease in risk, according to the second paper. But they were less likely to develop polyps that increase the risk, suggesting that a benefit may emerge later on, the researchers said.
The third paper found that the low-fat diet also did not significantly decrease the risk of breast cancer. Women on the low-fat diet did have 9 percent fewer breast cancers, but researchers could not be sure that difference was not the result of chance. There were other encouraging hints, however, including signs that women who were consuming the most fat when the study began, or those prone to certain types of tumors, may benefit, especially if they were followed longer.
"I think women who are currently following a low-fat diet should be encouraged to do so. We didn't see any unfavorable effects," said Ross Prentice of the Fred Hutchinson Cancer Research Center in Seattle, who noted that the women on the diet also avoided gaining weight. "For women who are at high risk for breast cancer, they should talk it over with their physicians whether adopting a low-fat diet might be warranted."
But overall, the findings fell far short of warranting a broad recommendation for low-fat diets, several experts said.
"We had hoped that this approach would prove to be beneficial," said Barbara Howard of the MedStar Research Institute, who helped conduct the study. "I think we've learned that nutrition is never simple and there are no simple solutions."
© 2006 The Washington Post Company
Another study:
Study questions greater GI safety of COX-2 inhibitors
COX-2 selective inhibitors, such as rofecoxib (Vioxx) or celecoxib (Celebrex),
have been billed as pain relievers with a lower risk of upper gastrointestinal
side effects than conventional NSAIDs, but new research suggests that this may
not be the case.
In a study of data from 367 general practices in the UK, Dr. Julia Hippisley-Cox,
from the University of Nottingham in the UK, and colleagues found no consistent
evidence that the COX-2 selective inhibitors were less likely to cause upper GI
side effects than the standard NSAIDs.
The one possible exception: celecoxib. After adjusting for potential
confounders, celecoxib use was not associated with a significantly increased
risk of upper GI side effects. However, the authors believe that this may have
been because relatively few patients in the study were taking celecoxib and thus
statistical power was lacking.
The report also indicates that with the exception of diclofenac, the risk of
adverse GI effects with both NSAIDs and COX-2 inhibitors can be largely
eliminated through the use of ulcer healing drugs. This, the authors claim,
supports their contention that there is an elevated risk of GI side effects with
COX-2 inhibitors as a whole and that these agents "may not be as safe as
originally thought."
The study, which is reported in the British Medical Journal for December 3,
involved a comparison of COX-2 and general NSAID use among 9407 subjects who
experienced a peptic ulcer or hematemesis during a 5-year period and 88,867
matched controls who did not.
The overall rate of upper GI events was 1.36 per 1000 person-years, the report
indicates. Compared with nonuse, current use of either COX-2 selective or
conventional NSAIDs was associated with an increased risk of such events.
After adjustment for confounders, use of naproxen, diclofenac, and rofecoxib
remained significantly linked to GI events, whereas celecoxib use was not. As
noted, these elevated risks largely disappeared when ulcer healing drugs were
also used, except for diclofenac, which continued to raise the risk of events by
49%.
"Evidence of enhanced GI safety with any of the new COX-2 inhibitors
compared with the non-selective NSAIDs is lacking," the researchers
conclude.
"We think that these findings are consistent with prior information in that
they show an advantage for Celebrex" in terms of GI safety, Dr. Gail
Cawkwell, medical director for Celebrex at Pfizer, Inc., told Reuters Health.
"But, we are very disappointed that (the researchers) chose to present the
information in a manner that is not helpful for doctors and patients who are
trying to make important health decisions."
Dr. Cawkwell agreed that the low patient numbers in the current study make it
impossible to reach definitive conclusions about the GI safety of Celebrex, but
she said that several previous studies have found the drug to be safer than
conventional NSAIDs. She also noted that of the drugs evaluated, only Celebrex
had a GI risk that was not significantly altered by the use of ulcer healing
drugs, further supporting the drug's greater safety.
Representatives from Merck, the embattled maker of the recently withdrawn Vioxx,
could not be reached for direct comment, but left this statement: "Results
from observational or epidemiological studies should be interpreted within the
context of all available data, particularly results from randomized, controlled
clinical trials. In a large, outcome trial (VIGOR), VIOXX 50 mg, twice the
maximum dose recommended for chronic use, was associated with a significantly
reduced risk of clinical upper GI events and complicated events compared to a
common clinical dose of naproxen."
BMJ 2005;331:1310-1312.
The above message comes from "Reuters Health", who is solely responsible for its content.
Also try this link to February 5 Washington Post on Medicare
http://www.washingtonpost.com/wp-dyn/content/article/2006/02/04/AR2006020401179_pf.html
Also try this latest link to the Washington Post: February 4, 2006: http://www.washingtonpost.com/wp-dyn/content/article/2006/02/03/AR2006020302598.html?referrer=email&referrer=email
ALSO:
Paxil/Paxil CR (paroxetine HCl) Public Health
Advisory: Exposure in the first trimester of pregnancy may increase the risk for
congenital malformations, particularly cardiac malformations
The FDA has determined that exposure to paroxetine in the first trimester of
pregnancy may increase the risk for congenital malformations, particularly
cardiac malformations. At the FDA's request, the manufacturer has changed
paroxetine's pregnancy category from C to D and added new data and
recommendations to the WARNINGS section of paroxetine's prescribing information.
FDA is awaiting the final results of the recent studies and accruing additional
data related to the use of paroxetine in pregnancy in order to better
characterize the risk for congenital malformations associated with paroxetine.
Physicians who are caring for women receiving paroxetine should alert them to
the potential risk to the fetus if they plan to become pregnant or are currently
in their first trimester of pregnancy. Discontinuing paroxetine therapy should
be considered for these patients. Women who are pregnant, or planning a
pregnancy, and currently taking paroxetine should consult with their physician
about whether to continue taking it. Women should not stop the drug without
discussing the best way to do that with their physician.
The above message comes from "FDA MedWatch", who is solely
responsible for its content.
* * *
Prescription Drugs Recently Taken Off U. S. Patent
Brand Drug Name Generic Name Month / Year Available
Retrovir 300mg tab zidovudine 300mg tab October 2005
Duricef suspension cefadroxil suspension October 2005
Accuzyme ointment allanzyme ointment September 2005
Panafil ointment allanfil ointment September 2005
Aclovate 0.05% cream alclometasone dipropionate 0.05% September 2005
Allegra 30mg, 60mg, 180mg tabs fexofenadine 30mg, 60mg, 180mg tabs September 2005
Arava 10mg and 20mg tabs leflunomide 10mg and 20mg tabs August 2005
Locoid 0.1% cream hydrocortisone butyrate 0.1% cream August 2005
Klonopin Wafers clonazepam rapidly disintegrating tabs August 2005
Keralac Cream urealac 50% cream July 2005
Carmol Scalp Treatment and 10% Lotion
sulfacetamide sodium scalp treatment and 10% lotion July 2005DDAVP 0.1mg and 0.2mg tablets desmopressin 0.1mg and 0.2mg tabs July 2005
OxyContin oxycodone ER June 2005
Lamictal 5mg and 25mg dispertabs lamotrigine 5mg and 25mg dispertabs June 2005
Elocon 0.1% lotion mometasone 0.1% lotion June 2005
Biaxin clarithromycin May 2005
Parlodel 5mg bromocriptine 5mg May 2005
Ultracet tramadol/acetaminophen May 2005
Climara 0.025mg and 0.075mg patch estradiol 0.025mg and 0.075mg patch April 2005
Locoid 1% ointment hydrocortisone butyrate 0.1% oint April 2005
Dantrium dantrolene April 2005
Anamantle HC lidocaine HC April 2005
Sporanox 100mg capsule itraconazole February 2005
Duragesic Patches fentanyl patches February 2005
Accupril quinapril December 2004
Neurontin 600mg,800mg gabapentin 600mg,800mg December 2004
Monopril HCT fosinopril/HCTZ December 2004
Foltx Folbic December 2004
Wellbutrin SR 200mg bupropion ER 200mg December 2004
Ultravate Cream, Ointment halobetasol cream, ointment December 2004
Videx EC 200mg,250mg,400mg didanosine DR 200mg,250mg,400mg December 2004
Pramosone 2.5% Cream HC pramoxine 2.5% cream November 2004
Celexa citalopram November 2004
Plendil felodipine November 2004
Depo-Provera medroxyprogesterone November 2004
Rev. 10/17/05
What are generic drugs?
A generic drug is called by its chemical name instead of the brand name chosen by the manufacturer for marketing purposes. For example, acetaminophen is the generic name and Tylenol is the brand name.
Unlike other “generic” products, such as generic foods found in the supermarket, generic drugs are required to have FDA approval, just like brand name drugs.
Can I get a generic version for all my prescription drugs?
Not all drugs have a generic version. Many drugs are protected by United States patents, which have not expired. Until the patent expires, the company, which owns the patent, is the only company who can produce that drug. Once the patent expires other companies can apply for approval to manufacture a generic version of the drug.
Who is the best source for information on which of my prescriptions has a generic version?
Physicians are best at choosing which drug is right for you, but they do not always know which drugs are available in a generic version. Your pharmacist is an excellent source for information on which of your prescriptions can be filled with a generic.
* This list contains common drug patent expirations. This list does not contain all US FDA drug patent expirations.
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