August 3, 2013

PLoS ONE 8(8): e71262. doi:10.1371/journal.pone.0071262

Open Access    Peer-Reviewed

Research Article

Georg Dultz, Martin Seelhof, Eva Herrmann, Martin-Walter Welker, Mireen Friedrich-Rust, Gerlinde Teuber, Bernd Kronenberger, Michael von Wagner, Johannes Vermehren, Christoph Sarrazin, Stefan Zeuzem, Wolf Peter Hofmann

Abstract

Background and Aims

In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined.

Methods

In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks).

Results

Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p = 0.015), mean platelets (102.64 vs. 138.95/nl, p = 0.014) and mean leukocytes (4.02 vs. 5.68/nl, p = 0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18–2.07; p = 0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6–9, 10–13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001).

Conclusions

Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.

Citation: Dultz G, Seelhof M, Herrmann E, Welker M-W, Friedrich-Rust M, et al. (2013) Baseline MELD Score Predicts Hepatic Decompensation during Antiviral Therapy in Patients with Chronic Hepatitis C and Advanced Cirrhosis. PLoS ONE 8(8): e71262. doi:10.1371/journal.pone.0071262

Editor: James Fung, The University of Hong Kong, Hong Kong

Received: February 28, 2013; Accepted: June 27, 2013; Published: August 1, 2013

Copyright: © 2013 Dultz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors have no support or funding to report.

Competing interests: The authors have declared that no competing interests exist.

Continue here to read full text …..

Statins may protect cirrhotic patients from infection

Provided by Healio

Motzkus-Feagans C. Aliment Pharmacol Ther. 2013;doi:10.1111/apt.12430.

August 2, 2013

Veterans with cirrhosis who used statins were at reduced risk for developing severe infection compared with nonusers, according to recent results.

In a retrospective cohort study, researchers evaluated data from 19,379 veterans with cirrhosis without decompensation, collected from the US Veterans Health Administration’s Austin Information Technology Center database between 2001 and 2009. In an additional, propensity-matched analysis, new statin users were matched equally against nonusers (n=1,760) and those receiving other cholesterol-lowering therapies (n=503). Incidence of infection and hospitalization was observed during a median 1,194 days of follow-up.

Approximately 13% of participants were statin users. Serious infection occurred in 12.4% of patients, including 946 cases of pneumonia, 866 skin infections, 171 bacteremia infections, 143 of septicemia, 131 cases of Clostridium difficile, 73 cases of spontaneous bacterial peritonitis/peritonitis and 32 urinary tract infections (UTI). Time to infection ranged from 394 days (kidney infections/UTI) to 1,057 days (systemic inflammatory response syndrome). Liver transplantation was performed in 0.5% of cases, and 0.1% of participants died during follow-up.

Use of statins (adjusted HR=0.42; 95% CI, 0.36-0.48) and other cholesterol medications (aHR=0.44; 95% CI, 0.33-0.61) was associated with reduced risk for infection, after adjusting for age, race, year of cohort entry, hepatitis C status, cirrhosis etiology, comorbidities and use of concurrent medications. In the propensity-matched analysis, risk for infection or death was lower among statin users compared with nonusers (aHR=0.67; 95% CI, 0.47-0.95), and an observed risk reduction for statin users compared with those on other cholesterol-lowering therapies trended toward significance (aHR=0.77; 95% CI, 0.31-1.94).

“One of statins’ many potential benefits, aside from cholesterol lowering, is the potential to reduce infections in patients with cirrhosis,” researcher Christine Motzkus-Feagans, MPH, department of quantitative health sciences at University of Massachusetts Medical School, told Healio.com. “While the evidence is still unclear, the data are suggestive of a link to reduced infections in patients taking statins. This is important because infections, especially those related to hospitalizations that were studied here, are one of the highest causes of death in cirrhosis.”

Disclosure: Researcher K. L. Lapane has served as a consultant for Ortho-McNeil Janssen Scientific Affairs.

Source

Download the PDF here

Download the PDF here

JAMA July 10 2013

Of the 30 leading diseases and injuries contributing to DALYs, 10 (COPD, major depressive disorders, othermusculoskeletal, diabetes, drug use disorders, Alzheimer, falls, cirrhosis, CKD, and osteoarthritis) increased by more than 30% from 1990 to 2010 (eTable 6 in the Supplement provides detail for the 272 diseases and injuries). Other disorders contributing to DALYs not in the top 30 that have also increased by more than 30% in the past 2 decades include liver cancer, atrial fibrillation, kidney cancers, eating disorders, and poisoning.

DALYs disability-adjusted life-years
HALE healthy life expectancy
YLDs years lived with disability
YLLs years of life lost due to premature mortality

DIET

In this analysis, the aggregate of the 14 subcomponents of diet is a more important factor associatedwith disease burden than either physical inactivity or high BMI.

The next 3 leading diseases contributing to YLLs, diabetes, cirrhosis and Alzheimer disease, all increased in rank and the number of YLLs from1990 to 2010. Colorectal cancer (10th), breast cancer (13th for both sexes combined and fifth in women), and pancreatic cancer (18th) are in the top 20 diseases and injuries contributing to premature death. Other large increases in premature mortality were seen for drug use disorders (moving from 44th to 15th), chronic kidney disease (CKD) (from 21st to 16th), kidney cancer (from 35th to 24th), and poisonings (from 31st to 26th); falls (from 33rd to 29th) and liver cancer (from 39th to 30th) also increased. The increase in YLLs associated with liver cancer may be related to a hepatitis C cohort effect.50 Among the 30 leading diseases and injuries contributing to YLLs in 1990, declines of 25% or more were seen for interpersonal violence, preterm birth complications, congenital anomalies, HIV/AIDS, and sudden infant death syndrome.

The YLLs related to HIV decreased by 64% and declined in rank from seventh to 23rd. eTables 3 and 4 in the Supplement provide estimates of deaths and YLLs, respectively, for all 223 diseases and injuries.

Continue to full article here for charts and tables …..

logo-prn-01_PRN

Public Sector Patients Rely on Government-Sponsored Programs to Cover HBV Drug Costs, Making it Critical for Manufacturers to Gain Inclusion in Government Formularies, According to a New Report from Decision Resources

BURLINGTON, Mass., Aug. 1, 2013 /PRNewswire/ -- Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that nearly 60 percent of surveyed physicians from Brazil, Mexico and Argentina report increases in the number of newly diagnosed hepatitis B virus (HBV) patients in their practices in the past two years. However, the majority of the seroprevalent HBV population in these markets remains undiagnosed and many patients are undertreated.

(Logo: http://photos.prnewswire.com/prnh/20130103/MM36784LOGO)

The Emerging Markets Physician & Payer Forum report entitled Positioning of Current and Emerging Agents for Hepatitis B Virus: Physician and Payer Perspectives on the Prescribing and Patient Access Landscape in Brazil, Mexico and Argentina finds that government-sponsored programs in Brazil and Argentina (Brazil's Specialized Program for Pharmaceutical Assistance and Argentina's Single Refund System) allow some patients to access a selection of fully covered HBV drugs. While most nucleotide analogues for HBV enjoy full coverage under these programs in Brazil and Argentina, no comparable government-sponsored programs yet exist in Mexico for HBV. Thus, Mexican HBV-infected patients not covered by Social Security often must pay out of pocket for treatment. Notably, the report finds that 61-79 percent of public HBV patients in the three markets rely entirely on government sponsorship to pay HBV drug costs. Surveyed physicians indicate that less than a quarter of patients receiving Gilead's Viread, or Bristol-Myers Squibb's Baraclude, are accessing these brands via private health insurance.

"All of the countries discussed in our report perform health technology assessment (HTA) evaluations to guide decisions on inclusion in government and social security drug formularies, either through national or institutional HTA bodies," said Decision Resources Product Manager Andreia Ribeiro, Ph.D. "New drugs need to establish not only a strong safety and efficacy profile, but they must also demonstrate value in terms of improved cost-benefit over current therapies to be included in formularies."

Several therapies may impact the HBV markets in Brazil, Mexico and Argentina during the next few years, including Bristol-Myers Squibb's PEG-IFN-lambda-1a and biosimiliars of PEG-IFN-alpha (Roche's Pegasys; Merck's PegIntron). More than 50 percent of public-sector surveyed physicians, and a sizeable proportion in the private sector, say that their hospital/institution will encourage prescribing of biosimilar agents, but that physicians will be able to prescribe a brand-name drug if they choose. Thus, near-term HBV market dynamics will hinge on emerging drug manufacturers' ability to provide compelling comparative clinical data versus reference products and their competitive suggested pricing.

About Decision Resources
Decision Resources (www.decisionresources.com) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources Group company.

About Decision Resources Group
Decision Resources Group is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources Group at www.DecisionResourcesGroup.com.

All company, brand, or product names contained in this document may be trademarks or registered trademarks of their respective holders.

SOURCE Decision Resources

RELATED LINKS
http://www.decisionresources.com

Source

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

For Immediate Release: Friday, August 2, 2013

NIH-funded study says five-marker genotype panel can guide ondansetron use

An experimental treatment for alcohol dependence works better in individuals who possess specific combinations of genes that regulate the function and binding of serotonin, a brain chemical affected by the treatment, according to a study supported by the National Institutes of Health. A report of the finding appears online in the American Journal of Psychiatry.

“This study is another important step toward personalized treatments for alcohol dependence,” says Kenneth R. Warren, Ph.D., acting director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), which funded the study. “A personalized approach based on a person’s genetic makeup is increasingly being investigated for delivering optimum treatment to the ‘right’ patient.”

Ondansetron is a medication currently used to treat nausea and vomiting, often following chemotherapy. It works by blocking serotonin-3 receptors, and has shown potential as a treatment for defined subpopulations with alcohol dependence.

In previous studies, Professor Bankole Johnson, D.Sc., M.D., and his team at the University of Virginia, Charlottesville, have shown that variations in genes that encode the serotonin transporter, a protein that regulates the concentration of serotonin between nerve cells, can significantly influence drinking intensity. They have also shown that the effectiveness of ondansetron therapy among people with alcohol dependence is influenced by variations of the serotonin transporter gene.

In the current study, Professor Johnson and his colleagues extended their prior work by analyzing variants of serotonin receptor genes, collectively designated as HTR3, among nearly 300 alcohol-dependent individuals who were participating in a clinical trial of ondansetron. They found that three HTR3 variants were significantly associated with the effectiveness of ondansetron treatment for alcohol dependence.

“Taken together, these studies implicate a collective effect of serotonin receptor and transporter gene combinations, defined by a five-marker genotype panel, on the response to treatment with ondansetron for a genetically defined subpopulation of individuals with alcohol dependence,” says Professor Johnson. “Multi-site, larger studies are about to begin to progress this work.”

The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at http://www.niaaa.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH...Turning Discovery Into Health®

Reference

Determination of genotype combinations that can predict the outcome of the treatment of alcohol dependence using the 5-HT3 antagonist ondansetron. Johnson, BA, et al. American Journal of Psychiatry. 2013 July 30. [Epub ahead of print]

Source

Public release date: 2-Aug-2013
Contact: Mount Sinai Press Office
newsmedia@mssm.edu
212-241-9200
The Mount Sinai Hospital / Mount Sinai School of Medicine

System represents major advance in studying virus

By differentiating monkey stem cells into liver cells and inducing successful infection, researchers from the Icahn School of Medicine at Mount Sinai have shown for the first time that the hepatitis C virus (HCV) can replicate in monkeys, according to research published in the journal Gastroenterology. The new findings may lead to the first new animal model and provide new avenues for developing treatments and vaccines for this disease, which impacts more than three million people in the United States.

Scientists have tried for decades to develop animal models to study HCV, but the virus was incapable of infecting any species except for humans and chimpanzees. With a recent National Institutes of Health-imposed moratorium restricting chimpanzee research, the Mount Sinai research team turned to a close relative of chimpanzees and humans—macaques. Led by Matthew Evans, PhD, and Valerie Gouon-Evans, PhD, of Mount Sinai, the research team sought to find out why previous attempts to infect macaques with HCV failed.

Dr. Gouon-Evans, who is Assistant Professor of in the Department of Developmental and Regenerative Biology at Mount Sinai, worked with a team at the Fred Hutchison Cancer Research Center in Seattle to differentiate macaque stem cells into liver cells. Dr. Evans, who is an Assistant Professor in the Department of Microbiology, and his team then attempted to infect these cells with HCV in a petri dish. They found that these differentiated cells were able to support HCV infection and replication, although not as effectively as in human liver cells.

"Now that we know that HCV infection in macaque cells is possible, we wanted to find out why it only worked in liver cells that were derived from stem cells," said Dr. Gouon-Evans. "By identifying where in the viral life cycle the infection is dysfunctional, we can develop an effective animal model of HCV."

Dr. Evans and his team found that HCV was less efficient at entering macaque cells to initiate infection compared to human cells because changes in the macaque form of a certain cell surface receptor rendered it less functional than the human version. This cell entry block could be overcome by expressing the human version of this receptor in macaque cells. Furthermore, HCV infection of normal macaque cells was greatly enhanced by changes to the virus that loosened its requirements for that receptor.

"Our discovery shows that by manipulating either host or viral genetics we can efficiently infect macaque cells," said Dr. Evans. "These findings may open doors for the field of HCV research, lead to new animal models, and hopefully vaccines and therapies."

Next, Dr. Evans plans to take these experiments out of petri dishes by attempting to infect macaques in vivo with the mutant HCV that can use the receptors this animal naturally expresses. If successful, this work would provide a new, much-needed animal model for HCV studies and vaccine development.

###

This work was supported by the Pew Charitable Trust.

Source

Janssen HCV Drug Research & Development

Provided by NATAP

Reported by Jules Levin

In the Spring Janssen & Gilead submitted New Drug Applications to the FDA requesting approval. The FDA hearing appears to be scheduled for Oct 24-25.

A Study of the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of JNJ-47910382 at Different Doses and Dose Regimens in Asian Genotype-1, Chronic, HCV-Infected Patients

Study in HCV-Infected Patients to Determine the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of JNJ-47910382

A Study in Healthy Participants Investigating the Safety, Tolerability and Plasma Pharmacokinetics (PK) of Single Oral Doses of JNJ-47910382

IDX719 in Combination With Simeprevir and Ribavirin for 12 Weeks in Subjects With Chronic Hepatitis C Infection
http://www.clinicaltrials.gov/ct2/show/NCT01852604?term=Janssen+AND+Hepatitis+C&recr=Open&no_unk=Y&rank=9

Antiviral Drugs Advisory Committee .........October 24-25
http://www.fda.gov/AdvisoryCommittees/Calendar/ucm153468.htm

Simeprevir (TMC435) with peginterferon/ribavirin for chronic hCV genotype 1 infection in treatment-naïve patients: results from QUEST-1, a Phase III trial
http://www.natap.org/2013/EASL/EASL_10.htm

Simeprevir (TMC435) with peginterferon-α2a or -α2b and ribavirin in treatment-naïve HCV genotype 1 patients: QUEST-2, a randomised Phase III trial
http://www.natap.org/2013/EASL/EASL_18.htm

Simeprevir with Peginterferon/ribavirin for Treatment of Chronic HCV Genotype 1 Infection in Patients Who Relapsed After Previous Interferon-based Therapy: Results from PROMISE, a Phase III Trial
http://www.natap.org/2013/DDW/DDW_06.htm

COSMOS Study: SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders
http://www.natap.org/2013/CROI/croi_34.htm

Medivir Press Release: New Drug Application has been filed with FDA for Simeprevir (TMC435) for combination treatment of adult patients with genotype 1 chronic hepatitis C
http://www.natap.org/2013/HCV/040213_01.htm

Idenix Pharmaceuticals Announces Initiation of Phase II All-Oral Combination Study of Samatasvir (IDX719) and Simeprevir (TMC435) for the Treatment of Hepatitis C Virus (HCV) Infection
http://www.natap.org/2013/HCV/060213_04.htm

Combination Therapy of TMC647055 With Simeprevir (TMC435) in Genotype 1 HCV Patients
http://www.natap.org/2013/EASL/EASL_41.htm

TMC055 Monotherapy data:
Human safety, pharmacokinetics and antiviral activity of TMC647055, a novel HCV non-nucleoside polymerase inhibitor.......
http://www.natap.org/2011/AASLD/AASLD_04.htm

Here is the link to the study on clinical trials.gov where you can see low dose 30mg RTV is used:
A Study to Evaluate the Safety, Tolerability, and Effectiveness of a 12-Week Combination Therapy of TMC647055 and TMC435 With a Pharmacokinetic Enhancer With and Without Ribavirin in Chronic Genotype-1 Hepatitis C Infected Patients.......http://clinicaltrials.gov/ct2/show/NCT01724086?term=tmc647055&rank=3

EASL: Combination Therapy of TMC647055 With Simeprevir (TMC435) in Genotype 1 HCV Patients - (04/30/13)

2nd generation NS5As

In Vitro Resistance Analysis of Merck's HCV NS5a Inhibitor MK-8742 Demonstrates Increased Potency AgainstClinical Resistance Variants and Improved Resistance Profile
http://www.natap.org/2012/EASL/EASL_46.htm

GS-5816, a Second-Generation HCV NS5A Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage, and a High Resistance Barrier
http://www.natap.org/2013/EASL/EASL_34.htm

Healthy Volunteer First-in-Human Evaluation of GS-5816, a Novel Second Generation Broad-Genotypic NS5A Inhibitor With Potential for Once-Daily Dosing - (04/29/13)

ACH-3102, A Second Generation NS5A Inhibitor, Demonstrates Potent Antiviral Activity in Patients with Genotype 1A HCV Infection Despite the Presence of Baseline NS5A-Resistant Variants - (05/09/13)

FINDINGS FROM CLINICAL VIROLOGY STUDIES ON ACH-3102 ARE CONSISTENT WITH PRECLINICAL OBSERVATIONS ON ITS IMPROVED POTENCY AGAINST GENOTYPE-1A HCV AND RESISTANT VARIANTS - (05/09/13)

No Clinically Significant Pharmacokinetic Interaction Between Sovaprevir and ACH-3102 in Healthy Volunteers - (05/09/13)

Synergistic Interactions of HCV NS5A Replication Complex Inhibitors Sensitize Resistant Variants and Enhance the Efficacy of Daclatasvir (DCV, BMS-790052) In Vitro and In Vivo - (04/27/13)

PRECLINICAL CHARACTERISTICS OF ACH-3102: A NOVEL HCV NS5A INHIBITOR WITH IMPROVED POTENCY AGAINST GENOTYPE-1A VIRUS AND VARIANTS RESISTANT TO 1ST GENERATION NS5A INHIBITORS
http://www.natap.org/2012/EASL/EASL_79.htm

Clinical

Source

Published on August 1, 2013 at 2:36 AM

The Food and Drug Administration's approval last year of the drug Truvada for prevention of HIV infection was a milestone in the fight against HIV/AIDS, but experts are cautioning that it is only the beginning of new ethical concerns for health care professionals, policy makers, researchers and those taking Truvada to prevent HIV infection.

"For the first time, we will have a large number of individuals who are not infected with HIV taking medication for HIV, which introduces ethical concerns of well-being and justice," says Jeremy Sugarman, Deputy Director for Medicine at the Johns Hopkins Berman Institute of Bioethics. He and Kenneth Mayer, the director of HIV prevention research at Beth Israel Deaconess Medical Center, advocate for ethical issues to be considered along with medical data in the Journal of Acquired Immune Deficiency Syndromes.

Sugarman and Mayer argue it is ethically critical to ensure that use of an antiretroviral drug like Truvada for "pre-exposure prophylaxis"(PrEP) does not have the ironic consequence of making individuals and communities less safe and healthy. Inconsistent, rather than daily, use of PrEP could result in HIV transmission and the evolution of drug-resistant strain of HIV, the authors warn. Likewise, misunderstanding of PrEP's prevention capacity could lead to the spread of other sexually transmitted infections.

"Communication and careful monitoring by health care professionals is essential for PrEP to be successful," says Sugarman. "Reinforcing the importance of daily dosing, incorporating safer sex counseling and frequent HIV testing will help meet the moral imperative that HIV be prevented and not exacerbated by PrEP," he says. He and Mayer recommend training programs for health care professionals that include explicit consideration of PrEP's ethical issues and their management.

Additionally, Sugarman and Mayer highlight what they say are 'critical, unanswered questions' of access and allocation. When limited antiretroviral drugs are available, should prevention be prioritized over treatment for those already infected with HIV, or vice-versa? Is a clinic environment the best setting to provide necessary counseling as part of PrEP? These questions, as well as how much PrEP should cost and who should pay for it, need to be answered as PrEP continues to be used and evaluated, the authors say.

"The fundamental moral claim for using PrEP, or any other HIV prevention strategy, is decreasing the burden of new HIV infections," Sugarman says. "For PrEP's full promise and medicine's moral obligations to be fulfilled, these complex ethical issues must be monitored along with the performance of PrEP."

Source: Johns Hopkins Medicine

Source

Page Last Updated: 08/01/2013

FDA Drug Safety Communication: FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen

View and print full Drug Safety Communication1 (PDF - 130KB)

Safety Announcement

[8-1-2013]  The U.S. Food and Drug Administration (FDA) is informing the public that acetaminophen has been associated with a risk of rare but serious skin reactions.  These skin reactions, known as Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), can be fatal.  Acetaminophen is a common active ingredient to treat pain and reduce fever; it is included in many prescription and over-the-counter (OTC) products.

Reddening of the skin, rash, blisters, and detachment of the upper surface of the skin can occur with the use of drug products that contain acetaminophen.  These reactions can occur with first-time use of acetaminophen or at any time while it is being taken.  Other drugs used to treat fever and pain/body aches (e.g., non-steroidal anti-inflammatory drugs, or NSAIDS, such as ibuprofen and naproxen) also carry the risk of causing serious skin reactions, which is already described in the warnings section of their drug labels.

Anyone who develops a skin rash or reaction while using acetaminophen or any other pain reliever/fever reducer should stop the drug and seek medical attention right away.  Anyone who has experienced a serious skin reaction with acetaminophen should not take the drug again and should contact their health care professional to discuss alternative pain relievers/fever reducers.

Health care professionals should be aware of this rare risk and consider acetaminophen, along with other drugs already known to have such an association, when assessing patients with potentially drug-induced skin reactions.

This new information resulted from the Agency’s review of the FDA Adverse Event Reporting System (FAERS) database and the medical literature1-20 to evaluate cases of serious skin reactions associated with acetaminophen (see Data Summary).  It is difficult to determine how frequently serious skin reactions occur with acetaminophen, due to the widespread use of the drug, differences in usage among individuals (e.g., occasional vs. long-term use), and the long period of time that the drug has been on the market; however it is likely that these events (i.e., SJS, TEN, and AGEP) occur rarely.

FDA will require that a warning be added to the labels of prescription drug products containing acetaminophen to address the risk of serious skin reactions.  FDA will also request that manufacturers add a warning about serious skin reactions to the product labels of OTC acetaminophen drug products marketed under a new drug application and will encourage manufacturers of drug products marketed under the OTC monograph do the same.

FDA has prepared a list of questions and answers2 to provide more information about this safety issue.

Facts about acetaminophen

  • It is widely used in both prescription and over-the-counter (OTC) products to reduce pain and fever.
  • It is available in single-ingredient drug products and in fixed-dose combination drug products (i.e., a combination of two or more ingredients in a single drug product).

Additional Information for Patients and Consumers

  • Acetaminophen is available alone in single-ingredient products and also combined with other medicines in products used to treat colds, coughs, allergies, pain, and sleeplessness.
  • Acetaminophen is an ingredient in many over-the-counter (OTC) and prescription medicines.  On OTC medicines, the word “acetaminophen” appears on the front of the package and on the Drug Facts label under the Active Ingredient(s) section.  On prescription medicines, the label may spell-out acetaminophen or it may have a shortened version of it such as “APAP,” “acet,” “acetamin,” or “acetaminoph.”  If you aren’t sure if your medicine contains acetaminophen, ask a pharmacist or your health care professional for additional information. 
  • Acetaminophen may rarely cause serious skin reactions.  Symptoms may include skin reddening, rash, blisters, and the upper surface of the skin may become separated from the lower layers.
  • Serious skin reactions can occur even if you have taken acetaminophen in the past without any problems.
  • If you develop any skin rash or reaction while using a medicine containing acetaminophen, stop the medicine and seek medical attention immediately.  A health care professional will evaluate you to determine if you are experiencing a serious skin reaction.  
  • If you have had a serious skin reaction with acetaminophen, do not take it or any products containing acetaminophen again.  Doing so could cause you to have another serious skin reaction.
  • Talk to your health care professional if you have any questions or concerns about acetaminophen or other pain relievers/fever reducers.
  • Other medicines used to treat fever and pain/body aches (e.g., non-steroidal anti-inflammatory drugs, or NSAIDs, such as ibuprofen and naproxen) also carry the risk of causing serious skin reactions.  However, having experienced a serious skin reaction with acetaminophen does not necessarily mean that you will also experience the reaction with other pain reliever/fever reducer medicines.
  • Report side effects from acetaminophen to the FDA MedWatch program, using the information in the Contact FDA box at the bottom of this page.

Additional Information for Health Care Professionals

  • Rarely, acetaminophen can cause serious, potentially fatal skin reactions, such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN).
  • The evidence supporting causality primarily comes from a small number of cases published in medical literature in which patients were rechallenged with acetaminophen and had a recurrence of the serious skin reaction.1-3  Other supportive data include reports from the FDA Adverse Event Reporting System (FAERS) database and case control studies (see Data Summary).21-26
  • Inform patients about the signs of serious skin reactions and that use of acetaminophen should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
  • Inform patients that acetaminophen may be an ingredient in over-the-counter (OTC) and prescription fixed-dose combination drug products, including those used to treat colds, coughs, allergy, pain, and sleeplessness.
  • Other drugs used to treat fever and pain/body aches (e.g., NSAIDs) also carry the risk of causing serious skin reactions.  However, there does not appear to be cross-sensitivity between acetaminophen and other pain reliever/fever reducer drugs.
  • Report adverse events involving acetaminophen to the FDA MedWatch program, using the information in the Contact FDA box at the bottom of this page.

Data Summary

FDA reviewed the FDA Adverse Event Reporting System (FAERS) database and the medical literature for evidence of an association between acetaminophen and Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP).  The evidence supporting causality between acetaminophen and serious skin reactions primarily comes from a small number of published cases in which patients were rechallenged with acetaminophen and had a recurrence of a serious skin reaction.1-3

  • In one case, a 7-year-old girl with fever and sore throat was treated with three doses of acetaminophen (10 mg/kg), and 12 hours later, she developed an erythematous rash over her gluteal region and legs.  Her condition worsened, and she was admitted to a hospital.  Her skin biopsy was compatible with TEN.  Six months later, an allergist questioned the diagnosis of TEN due to acetaminophen and performed an oral rechallenge with acetaminophen 250 mg.  No other drugs were used.  Thirty minutes later, the patient developed diffuse urticaria and erythema and was readmitted to the hospital.1
  • In another case, an 11-year-old boy was hospitalized for SJS.  He had taken acetaminophen for a cold and presented to medical attention with malaise, fever, and erythematous macules that progressed to erosive, hemorrhagic lesions.  Laboratory testing included a biopsy that was compatible with SJS.  A later oral test with acetaminophen (clinicians were unaware the original reaction was associated with acetaminophen) resulted in erythema multiforme, diagnosed clinically with a compatible biopsy.2
  • In a third case, an 83-year-old man took acetaminophen and multiple other drugs for a hip replacement.  He was admitted to the hospital with an erythematous rash with hundreds of small, nonfollicular pustules; biopsy showed subcorneal pustules, spongiosis, papillary edema, and a perivascular infiltrate consistent with AGEP.  All drugs were stopped with resolution of the eruption and widespread desquamation.  Skin patch tests with acetaminophen only resulted in subcorneal pustules.  He experienced a recurrence of AGEP with subsequent administration of intravenous propacetamol, a prodrug of acetaminophen.3

In addition to the three positive rechallenge cases, the medical literature contained several cases of SJS, TEN, and AGEP (3, 17, and 6 cases, respectively) in which the only drug administered prior to the reaction was acetaminophen, or acetaminophen hypersensitivity was demonstrated by skin testing or other means.1-20  There were no deaths reported in the literature, but the majority of cases required hospitalization.  All cases resolved with discontinuation of the drug.

A search of FAERS from 1969 to 2012 identified 91 cases of SJS/TEN and 16 cases of AGEP, which resulted in 67 hospitalizations and 12 deaths.  The majority of the cases involved single-ingredient acetaminophen products.  A small number of cases involved injectable acetaminophen products or oral acetaminophen/opioid fixed-dose combination products.  Indications for acetaminophen use varied between pyrexia and analgesia, and the majority of the reported doses were consistent with labeled dosing recommendations.

Of the 91 cases of SJS/TEN, 6 were categorized as probable cases associated with acetaminophen, with the rest categorized as possible cases.  Of the 16 cases of AGEP, 1 was categorized as a probable case associated with acetaminophen, with the rest categorized as possible cases.  These seven probable cases had a confirmed diagnosis of SJS/TEN or AGEP by a dermatologist and/or histological findings temporally associated with acetaminophen; confounding medications were not administered within two weeks preceding the events.  The time to event, which was measured from the initiation of acetaminophen to the onset of cutaneous signs and symptoms, ranged from less than 24 hours to 8 days.  Among these probable cases, six people were hospitalized and one died.

FDA’s review of five SJS/TEN case-control studies and one of AGEP indicated that risks of SJS/TEN may be increased with the use of acetaminophen and were generally independent of the effects of other drugs.21-26  However, all but two of these case control studies failed to address the possible presence of protopathic bias, which in this setting refers to a false increase in the risk of SJS/TEN attributable to acetaminophen, due to its use to treat fever, a prodromal symptom of SJS/TEN.  In one of the two studies that controlled for the confounding effect of protopathic bias by limiting the acetaminophen exposure period to a time preceding the prodromal period, acetaminophen remained significantly associated with SJS/TEN.26

References

  1. Halevi A, Ben-Amitai D, Garty BZ. Toxic epidermal necrolysis associated with acetaminophen ingestion. Ann Pharmacother 2000;34:32-4.
  2. Trujillo C, Gago C, Ramos S. Stevens-Johnson syndrome after acetaminophen ingestion, confirmed by challenge test in an eleven-year-old patient. Allergol Immunopathol (Madr) 2010;38:99-100.
  3. Leger F, Machet L, Jan V, Machet C, Lorette G, Vaillant L. Acute generalized exanthematous pustulosis associated with paracetamol. Acta Derm Venereol 1998;78:222-3.
  4. Bygum A, Gregersen JW, Buus SK. Acetaminophen-induced toxic epidermal necrolysis in a child. Pediatr Dermatol 2004;21:236-8.
  5. Bouziri A, Khaldi A, Hamdi A, Borgi A, Ghorbel S, Kharfi M, et al. Toxic epidermal necrolysis complicated by small bowel intussusception: a case report. J Pediatr Surg 2011;46:e9-11.
  6. Reese D, Henning JS, Rockers K, Ladd D, Gilson R. Cyclosporine for SJS/TEN: a case series and review of the literature. Cutis 2011;87:24-9.
  7. Dragojevic-Simic V, Vukovic J, Kovacevic A. Paracetamol-induced toxic epidermal necrolysis in adult: clinical pharmacology unit case report. Basic & Clinical Pharmacology & Toxicology. Volume 105(Supplement 1):98.
  8. Verneuil L, Ratajczak P, Allabert C, Leboeuf C, Comoz F, Janin A, et al. Endothelial cell apoptosis in severe drug-induced bullous eruptions. Br J Dermatol 2009;161:1371-5.
  9. Yamane Y, Aihara M, Tatewaki S, Matsukura S, Kanbara T, Yamakawa Y, et al. Analysis of treatments and deceased cases of severe adverse drug reactions--analysis of 46 cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Arerugi 2009;58:537-47.
  10. Pyo KS, Heung YD, Jung KS, Hyeong CS, Soo CN. A case of toxic epidermal necrolysis (TEN) induced by nonsteroidal anti-inflammatory drug (NSAID) in Emergency Medical Center. Toxicology Letters 2008;180(Supplement 5):S140.
  11. Yun SJ, Choi MS, Piao MS, Lee JB, Kim SJ, Won YH, et al. Serum lactate dehydrogenase is a novel marker for the evaluation of disease severity in the early stage of toxic epidermal necrolysis. Dermatology 2008;217:254-9.
  12. Gerdts B, Vloemans AF, Kreis RW. Toxic epidermal necrolysis: 15 years' experience in a Dutch burns centre. J Eur Acad Dermatol Venereol 2007;21:781-8.
  13. Prins C, Kerdel FA, Padilla RS, Hunziker T, Chimenti S, Viard I, et al. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 2003;139:26-32.
  14. Takeuchi Y, Katagiri K, Hatano Y, Fujiwara S. A case of toxic epidermal necrolysis due to acetaminophen. Sainichi Hifu 2004;56:1-10.
  15. Khare KC, Khare S, Mathew G. Stevens Johnson syndrome with keratitis following paracetamol injection. Indian J Dermatol Venereol Leprol 1997;63:209.
  16. Szepietowski J, Wasik F, Szybejko-Machaj G, Maj J. Toxic epidermal necrolysis successfully treated with cyclosporin: report of three cases. J Eur Acad Dermatol Venereol 1997;9:169-72.
  17. Sezer E, Sezer T, Koseoglu D, Filiz NO. Acute generalized exanthematous pustulosis in a child. Pediatr Dermatol 2007;24:93-5.
  18. Wohl Y, Goldberg I, Sharazi I, Brenner S. A case of paracetamol-induced acute generalized exanthematous pustulosis in a pregnant woman localized in the neck region. Skinmed 2004;3:47-9.
  19. Mashiah J, Brenner S. A systemic reaction to patch testing for the evaluation of acute generalized exanthematous pustulosis. Arch Dermatol 2003;139:1181-3.
  20. De Coninck AL, Van Strubarq AS, Pipeleers-Marichal MA, Huyghens LP, Suys ET, Roseeuw DI. Acute generalized exanthematous pustulosis induced by paracetamol. A case with severe hemodynamic disturbances. Dermatology 1996;193:338-41.
  21. Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995;333:1600-7.
  22. Sidoroff A, Dunant A, Viboud C, Halevy S, Bavinck JN, Naldi L, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational case-control study (EuroSCAR). Br J Dermatol 2007;157:989-96.
  23. Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol 2008;128:35-44.
  24. Gau SS, Chao PF, Lin YJ, Chang CJ, Gau CS. The association between carbamazepine and valproate and adverse cutaneous drug reactions in patients with bipolar disorder: a nested matched case-control study. J Clin Psychopharmacol 2008;28:509-17.
  25. Sassolas B, Haddad C, Mockenhaupt M, Dunant A, Liss Y, Bork K, et al. ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis. Clin Pharmacol Ther 2010;88:60-8.
  26. Levi N, Bastuji-Garin S, Mockenhaupt M, Roujeau JC, Flahault A, Kelly JP, et al. Medications as risk factors of Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a pooled analysis. Pediatrics 2009;123:e297-304.

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