viernes, 29 de enero de 2010

P. falciparum Malaria, Southern Algeria, 2007 | CDC EID



EID Journal Home > Volume 16, Number 2–February 2010

Volume 16, Number 2–February 2010
Dispatch
Plasmodium falciparum Malaria, Southern Algeria, 2007
Saïd C. Boubidi, Ibrahim Gassen, Yacine Khechache, Karima Lamali, Boualem Tchicha, Cécile Brengues, Michela Menegon, Carlo Severini, Didier Fontenille, and Zoubir Harrat
Author affiliations: Institut Pasteur, Algiers, Algeria (S.C. Boubidi, Z. Harrat); Prevention Centre, Tamanrasset, Algeria (I. Gassen); Institut National de Santé Publique, Algiers (Y. Khechache, B. Tchicha); Ministère de la Santé, Algiers (K. Lamali); Institut de Recherche et de Développement, Montpellier, France (C. Brengues, D. Fontenille); and Istituto Superiore di Sanità, Rome, Italy (M. Menegon, C. Severini)


Suggested citation for this article

Abstract
An outbreak of Plasmodium falciparum malaria occurred in Tinzaouatine in southern Algeria in 2007. The likely vector, Anopheles gambiae mosquitoes, had not been detected in Algeria. Genes for resistance to chloroquine were detected in the parasite. The outbreak shows the potential for an increase in malaria vectors in Algeria.

Outbreaks of malaria in southern Algeria have been observed for many years, including a major epidemic in Dajnet in 1928–1929 (1). Most (>90%) documented cases were attributed to Plasmodium falciparum (2); Anopheles sergenti and An. multicolor mosquitoes were incriminated as potential vectors (3). The Sahara Desert has been regarded as an effective barrier against northward expansion of An. gambiae mosquitoes, the main malaria vector in Africa, into Algeria. However, this mosquito has been detected near the Algeria–Mali border (4).

In recent years, marked changes in the environment and the economy of southern Algeria have occurred (exploitation of underground water resources, growth of the human population in several oases, and development of a transport infrastructure). The new Trans-Saharan Highway, which links Algeria and West Africa, is a potential route for introduction of tropical vectors and parasites into southern Algeria (2,5).

In November 2007, a total of 26 autochthonous cases of P. falciparum malaria were detected in Tinzaouatine, a village in Algeria near the Algeria–Mali border. We present results of a parasitologic and entomologic study conducted during the outbreak and discuss the potential for establishment of vectors and P. falciparum malaria in Algeria.

The Study
Tinzaouatine (altitude 620 m, 19.95°N, 2.96°E, population ≈12,000) is a village near the Mali border, ≈2,000 km south of Algiers and 578 km southeast of Tamanrasset. Most of its inhabitants are nomadic Tuareg. The climate is arid (annual mean temperature 27°C, range 17°C–33°C, <100 mm rain/year; Office Nationale de Météorologie, Algiers, Algeria). Precipitation is associated with the West African monsoon and restricted to a short period (June–September). The Tinzaouatine River, which is dry for most of the year, occasionally floods. After flooding, receding water results in abundant pools (gueltas) that are ideal breeding sites for anopheline mosquitoes. Livestock (mostly sheep and goats) are common in the region. However, no agricultural activity takes place and no irrigation system exists.

During a 2-week period in December 2007, adult mosquitoes were collected by morning indoor spraying in 4 houses and 3 nomad tents (2×/week), human landing catches (2 nights/week), and CDC light traps and mouth aspirators in resting sites (at night). Adult sampling was conducted in dwellings of persons with cases of malaria. Human landing catches were made on 2 adult volunteers from the medical research team from 8:00 pm to 6:00 am. Larvae and pupae were collected by dipping into 2 mosquito-positive pools (1× over a 3-hour period). Adult mosquitoes derived from pupae were identified by using morphologic keys (6) and genotyped by rDNA PCR to determine species within the An. gambiae complex (7).

Eleven pools were tested for anopheline larvae. However, many had been treated with insecticide. Larvae of anophelines and other species were collected from 2 gueltas (area 30 m2 and 200 m2, respectively). A total of 123 anopheline larvae were reared into adults (35 males and 12 females hatched). All specimens were of the Mopti (M) molecular form of An. gambiae sensu stricto mosquitoes. Use of entomologic controls at the same site in 2008 confirmed that the unique anopheline species present in this area was An. gambiae sensu lato. No adult mosquitoes were captured, probably because of insecticide spraying during the period of sampling to control the outbreak and because of a temperature <10°C at night.

Clinical diagnosis of malaria was made at the health center in the village. A total of 1,468 samples were examined by microscopy during the outbreak. Twenty-six patients (11 female and 15 male, age range 1–43 years) who had fever, chills, and rigor had samples positive for P. falciparum. None of these patients had traveled outside Tinzaouatine before the outbreak, which indicated that these cases were autochthonous.

All patients were treated with chloroquine (10 mg/kg/day for 2 days and 5 mg/kg for 3 days). Clinical resistance to chloroquine was not reported and no deaths occurred. Informed consent was obtained from each patient or adult guardian of children enrolled in this study at the time of blood collection.

Ten samples were chosen for molecular study; 8 were from patients positive by microscopy and 2 were from patients with malaria symptoms negative for P. falciparum by microscopy. Samples were processed by placing a drop of blood on filter paper. Molecular analysis was conducted according to the protocol described by Snounou et al. (8). Molecular screening by real-time PCR was used to detect mutations in the P. falciparum dihydrofolate reductase (dhfr), dihydropteroate synthase (dhps), and chloroquine resistance transporter (crt) genes, which are involved in P. falciparum drug resistance (9). Molecular analysis results of 5 PCR-positive blood samples showed the pfcrt 76T and the dhfr 108N mutations, and 4 showed the quadruple mutation (dhfr 51I, 59R, 108N and dhps 436A). No mutations were detected in the dhps 540 codon. We also identified a P. falciparum isolate with a unique sextuple drug resistance profile (Y86mdr1/T76crt/I51dhfr/R59dhfr/N108dhfr/A436dhps).

Although all patients were treated with chloroquine and despite our evidence of polymorphisms in genes linked to chloroqunie resistance, no clinical failures were observed. Polymorphisms in the crt gene are strongly associated with chloroquine resistance. Involvement of the mdr1 gene in chloroquine resistance has been challenged, but variation at codon 86 of this gene modulates resistance to chloroquine (10).

Conclusions
An average of 300 cases of malaria is recorded in cities in southern Algeria every year, mostly in Tamanrasset and Adrar. Parasites are introduced by infected humans; >90% of cases originate in Mali and Niger (11). Several autochthonous infections have been reported in Tinzaouatine (Table). We suggest that introduction of malaria into this area likely reflects the highly mobile nature of local populations and associated travel to or from areas endemic for malaria. Interethnic conflicts in northern Mali have also increased the displacement of populations toward Algeria.

An. gambiae mosquitoes in Algeria probably originated in Mali. Algeria has borders with Mali and Niger, countries where An. gambiae sensu lato mosquitoes are present (4). The most likely mode of introduction of An. gambiae mosquitoes into Algeria is passive transport by vehicles and trucks because considerable traffic moves across its borders (12). An alternative hypothesis is that mosquitoes were carried by wind from breeding sites in southern Mali, a mode of dispersal that has been described for other species of mosquitoes (13).

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P. falciparum Malaria, Southern Algeria, 2007 | CDC EID
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The February 2010 MedSun Newsletter


Highlighted articles include:
please, see here:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/medsun/news/newsletter.cfm?news=45#1

Hettich Centrifuges with 2050 and 2076 Plastic Rotors: Recall
The plastic centrifuge rotor may crack, break apart and be forcefully ejected through the plastic centrifuge housing at a high rate of speed...

Edwards Lifesciences Aquarius Hemodialysis System: Recall
Reports of clinically significant fluid imbalance and the potential for users to repeatedly override the fluid imbalance alarm...

Infusion Set Needles [Manufactured by Nipro for Exelint]: Recall
Recall due to 'coring', the cutting or dislodging of silicone cores or slivers from the ports into which they are inserted...

Nipro GlucoPro Insulin Syringes: Recall
Needles may detach from the syringe...

ev3 Endovascular Inc. Trailblazer Support Catheter: Class I Recall
Device may crack near the radiopaque marker band, possibly resulting in serious patient injury...


Rapamune (sirolimus): Drug Monitoring Recommendations
Changes in the performance of an immunoassay used for therapeutic drug monitoring (TDM) of Rapamune...


Interpretive Comments on Test Results: How Far Should Labs Go?
In order to help clinicians understand test results, some labs have started including interpretive comments on their lab reports...

Human factors and ergonomics in home care: Current concerns and future considerations for health information technology
Health information technologies are being promoted as possible solutions to human factors and ergonomic concerns for the home care nurse and patient, but these same technologies also bring a new set of concerns...

Children are Commonly Harmed by Adverse Events in Intensive Care Units
To improve safety in pediatric ICUs, the researchers recommend developing protocols for high-risk procedures involving lines and tubes; improved monitoring; and staffing, training, and communication initiatives...

Opinions on medicines for use outside the European Union - Aluvia



FICHA FARMACOLÓGICA de lopinavir / ritonavir Contiene las Revisiones Monográficas en idioma inglés únicamente (documentos de la Unión Europea), así como la discusión científica que sustenta su aprobación terapéutica. Para acceder a la monografía en idioma español [no aplica], hacer doble clik en la sigla (es) en la fila que se sitúa más abajo del centro de la página oficial [no aplica]. Se recuerda que todas las informaciones científico-clínicas, así como técnicas propias de la producción, sólo se publican en idioma inglés. Cerasale. ENERO 29, 2010.-

abrir aquí para acceder al documento EMEA completo:
Opinions on medicines for use outside the European Union - Aluvia

Active Substance
lopinavir / ritonavir
International Nonproprietary Name or Common Name
lopinavir / ritonavir
Pharmaco-therapeutic Group
Protease inhibitors
ATC Code
J05AE06

Therapeutic Indication:
Aluvia is indicated for the treatment of HIV-1 infected adults and children above the age of 2 years, in combination with other antiretroviral agents.

Most experience with Aluvia is derived from the use of the product in antiretroviral therapy naïve patients. Data in heavily pretreated protease inhibitor experienced patients are limited. There are limited data on salvage therapy on patients who have failed therapy with Aluvia.

The choice of Aluvia to treat protease inhibitor experienced HIV-1 infected patients should be based on individual viral resistance testing and treatment history of patients.


Orphan medicinal product designation date
Not applicable


Opinions on medicines for use outside the European Union

Agency for Healthcare Research and Quality (AHRQ) Medical Errors & Patient Safety Update--AHRQ Publishes Funding Announcements in Patient Safety-Relat


Agency for Healthcare Research and Quality (AHRQ) Medical Errors & Patient Safety Update--AHRQ Publishes Funding Announcements in Patient Safety-Related Areas

AHRQ Publishes Funding Announcements in Patient Safety-Related Areas
AHRQ announces the following new funding announcements and notices related to patient safety:
· Funding Opportunity Announcements
o Prevention and Management of Healthcare Associated Infections (R18): The purpose of this funding opportunity is to fund extramural health services research, demonstration, dissemination, and evaluation grants that propose to prevent and more effectively manage health care associated infections. This funding opportunity sets a multi-year research framework, based on the distillation of existing, peer-reviewed research, case studies, the Department of Health and Human Services’ 2009 National Action Plan on Healthcare-associated Infections, and qualitative information resulting from a series of listening sessions that occurred in selected cities across the United States in 2009. Application Due Date: March 29, 2010.
http://grants.nih.gov/grants/guide/pa-files/PA-10-089.html

o Improving Patient Safety through Simulation Research (R18): AHRQ announces the availability of grants to develop, test, and evaluate the impact of various simulation approaches for the purpose of improving the safe delivery of health care. The projects funded under this funding opportunity announcement will inform providers, health educators, payers, policy makers, patients, the public, and AHRQ about the effective use of simulation in improving patient safety. Application Due Date: March 26, 2010.
http://grants.nih.gov/grants/guide/rfa-files/RFA-HS-10-018.html


· Special Emphasis Notice
http://grants.nih.gov/grants/guide/notice-files/NOT-HS-10-009.html
AHRQ has recently issued a Special Emphasis Notice focused on career development grant opportunities for individuals who are focused on reducing and eliminating health care-associated infections (HAIs) within ambulatory health care settings. This includes acute care areas within hospitals, same-day surgery centers, dialysis centers, outpatient care clinics, and long-term care facilities such as nursing homes and rehabilitation facilities. Research priorities related to this notice are the:

o the development, implementation, and demonstration of strategies and interventions that prevent and manage HAIs, along with the determination of the costs of such interventions;
o determination of the efficacy and effectiveness of preventative interventions; and
o population-level studies on the patient risk factors, sources, and disease genotypes of antibiotic-resistant organisms that can result in HAIs.


· Individual Career Development Awards
AHRQ recently expanded its career development opportunities to include support for mentored research scientists. This opportunity will run parallel with our ongoing mentored clinical scientist program. We are also continuing our independent scientist development program, which is open to students pursuing either clinical or research doctorates.
o Mentored Research Scientists
http://grants.nih.gov/grants/guide/pa-files/PAR-08-022.html

o Mentored Clinical Scientists
http://www.ahrq.gov/fund/training/rsrchtng.htm#MCSDA

o Independent Scientist Awards
http://www.ahrq.gov/fund/training/rsrchtng.htm#ISA

AHRQ News and Numbers: January 29, 2010


January 29, 2010, Issue #286

AHRQ News and Numbers


Among the 36 percent of U.S. adults age 18 and older who needed to see a specialist in 2007, about 8 percent reported that getting to see one was a big problem. [Source: Agency for Healthcare Research and Quality, MEPS, Statistical Brief #274: Variations in Perceived Need and Access to Specialist Care among Adults in the U.S. Civilian Noninstitutionalized Population, 2007.] (PDF File) (PDF Help)
http://www.meps.ahrq.gov/mepsweb/data_files/publications/st274/stat274.pdf

Today’s Headlines:

1. AHRQ seeks nominations for the Effective Health Care Stakeholder Group
2. AHRQ and American College of Cardiology collaborate on study of implantable cardioverter defibrillators
3. Comparative effectiveness research grant awards
4. AHRQ seeks nominations for two future chairpersons of CERTs Steering Committee
5. Task Force recommendation on screening for obesity in children and adolescents
6. New AHRQ evidence report on tests for exercise-induced asthma and bronchoconstriction is available
7. AHRQ in the professional literature


1. AHRQ Seeks Nominations for the Effective Health Care Stakeholder Group

AHRQ’s Effective Health Care program is seeking nominations from interested organizations and individuals for members of the Stakeholder Group to support the work of comparative effectiveness, established [for consultations] pursuant to Section 1013 of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003. Individuals selected to the Stakeholder Group will serve a 2-year term, beginning the summer of 2010 and ending the summer of 2012. The deadline for receipt of nominations is February 8. Select to read the January 7 Federal Register notice.
http://edocket.access.gpo.gov/2010/E9-31341.htm


2. AHRQ and American College of Cardiology Collaborate on Study of Implantable Cardioverter Defibrillators

A $3.5 million research project that will study the long-term benefits and risks of implantable cardioverter defibrillators in patients at risk of death from ventricular fibrillation will be supported by AHRQ and the American College of Cardiology. The project is being conducted in cooperation with the National Heart, Lung (NHLBI), and Blood Institute, part of the National Institutes of Health. The new 3½ -year study will be conducted by members of the AHRQ-supported HMO Research Network, a consortium of 15 health care delivery systems that conduct research on various topics, including medical effectiveness and safety. The systems are also part of NHLBI’s Cardiovascular Research Network. The results will also be helpful to the Centers for Medicare & Medicaid Services, which has covered cardioverter defibrillators for certain patients since 2005 and has required that certain Medicare patients receiving the devices be enrolled in a national registry. Select to read our press release.
http://www.ahrq.gov/news/press/pr2010/accicdpr.htm


3. Comparative Effectiveness Research Grant Awards

AHRQ has developed Web page that contains general information about ongoing AHRQ-funded comparative effectiveness research projects. The Web page will be updated as future research grants are awarded. Select to access the Web page on the Effective Health Care program Web site.
http://www.effectivehealthcare.ahrq.gov/index.cfm/comparative-effectiveness-research-grant-awards/


4. AHRQ Seeks Nominations for Two Future Chairpersons of CERTs Steering Committee

AHRQ’s Centers for Education and Research on Therapeutics (CERTs) program is seeking qualified individuals to serve as future chairs of the National Steering Committee. AHRQ seeks two future Chairs to serve sequentially as Chairs-Elect. The deadline for receipt of nominations has been extended to February 16. Select to read the announcement.
http://www.ahrq.gov/clinic/certsnoms.htm


5. Task Force Recommendation on Screening for Obesity in Children and Adolescents

Based on new evidence that children and adolescents can be effectively treated for obesity, the U.S. Preventive Services Task Force now recommends that clinicians screen children ages 6 to 18 years for obesity and refer them to programs to improve their weight status. Comprehensive programs included 3 components: 1. counseling for weight loss or healthy diet; 2. counseling for physical activity or a physical activity program; and, 3. behavioral management techniques such as goal setting and self monitoring. Moderate- to high-intensity programs involve more than 25 hours of contact with the child and/or the family over a 6-month period. Families who seek treatment for obesity should look for comprehensive programs that address weight control through healthy food choices, physical activity and behavioral skill-building. The recommendation was released online on January 18 and will be published in the February issue of Pediatrics. Select to access the recommendation.
http://www.ahrq.gov/clinic/uspstf/uspschobes.htm


6. New AHRQ Evidence Report on Tests for Exercise-Induced Asthma and Bronchoconstriction Is Available

Exercise-induced asthma and bronchoconstriction affect millions of Americans who, after playing sports or exercising, experience shortness of breath, coughing, chest pain, and even nausea. While exercise-induced asthma occurs in up to 90 percent of people with asthma, exercise-induced bronchoconstriction also strikes those without asthma. Both exercise-induced asthma and bronchoconstriction often go undiagnosed and untreated. A number of tests have been developed to detect exercise-induced asthma and bronchoconstriction; however, only six provided sufficient evidence to contribute to a formal evaluation. None of these alternatives was as accurate as the standard “exercise challenge test,” which involves having the patient perform high-intensity exercise for six minutes, and tracking lung function following exercise to look for evidence of exercise-induced asthma and bronchoconstriction. The new report, Exercise-induced Brochoconstriction and Asthma, was prepared by the AHRQ’s University of Alberta Evidence-based Practice Center in Edmonton. Select to access the report.
http://www.ahrq.gov/clinic/tp/eibeiatp.htm


7. AHRQ in the Professional Literature

We are providing the following hyperlinks to journal abstracts through PubMed® for your convenience. Unfortunately, some of you may not be able to access the abstracts because of firewalls or specific settings on your individual computer systems. If you are having problems, you should ask your technical support staff for possible remedies.

Harrison MI, Kimani J. Building capacity for a transformation initiative: system redesign at Denver Health. Health Care Manage Rev 2009 Jan-Mar; 34(1):42-53. Select to access the abstract.
http://www.ncbi.nlm.nih.gov/pubmed/19104263

Lazarus R, Klompas M, Campion FX, et al. Electronic Support for Public Health: validated case finding and reporting for notifiable diseases using electronic medical data. J Am Med Inform Assoc 2009 Jan-Feb; 16(1):18-24. Select to access the abstract.
http://www.ncbi.nlm.nih.gov/pubmed/18952940


Neuman HB, Michelassi F, Turner JW, et al. Surrounded by quality metrics: what do surgeons think of ACS-NSQIP? Surgery 2009 Jan; 145(1):27-33. Select to access the abstract.
http://www.ncbi.nlm.nih.gov/pubmed/19081472


Prince JD, Akincigil A, Hoover DR, et al. Substance abuse and hospitalization for mood disorder among Medicaid beneficiaries. Am J Public Health 2009 Jan; 99(1):160-7. Select to access the abstract.
http://www.ncbi.nlm.nih.gov/pubmed/19008505


Glance LG, Osler TM, Mukamel DB, et al. Impact of statistical approaches for handling missing data on trauma center quality. Ann Surg 2009 Jan; 249(1):143-8. Select to access the abstract.
http://www.ncbi.nlm.nih.gov/pubmed/19106690

Bader JD, Perrin NA, Maupome G, et al. Exploring the contributions of components of caries risk assessment guidelines. Comm Dent Oral Epidemiol 2008 Aug; 36(4):357-62. Select to access the abstract.
http://www.ncbi.nlm.nih.gov/pubmed/19145722

Kuppermann M, Norton ME, Gates E, et al. Computerized Prenatal Genetic Testing Decision-Assisting Tool: randomized controlled trial. Obstet Gynecol 2009 Jan; 113(1):53-3. Select to access the abstract.
http://www.ncbi.nlm.nih.gov/pubmed/19104360

Please address comments and questions regarding the AHRQ Electronic Newsletter to Nancy Comfort at Nancy.Comfort@ahrq.hhs.gov or (301) 427-1866
file5000//january2010=496//

HIV/AIDS Update - Videx EC/Videx (didanosine) label change reflects potential for serious liver disorder



HIV/AIDS Update - Videx EC/Videx (didanosine) label change reflects potential for serious liver disorder

The Food and Drug Administration (FDA) is alerting healthcare professionals and patients about a rare, but serious, complication in the liver known as non-cirrhotic portal hypertension in patients using Videx or Videx EC (didanosine). Didanosine is a medication used to treat human immunodeficiency virus (HIV) infection.

Non-cirrhotic portal hypertension (portal hypertension that is not caused by cirrhosis of the liver) is rare in the United States. It occurs when blood flow in the major vein in the liver (the portal vein) slows down. This slowed blood flow can lead to the development of severely enlarged esophageal veins (varices) in the gastrointestinal system. Because esophageal varices are thin and portal hypertension increases the pressure of blood flow in these veins, esophageal varices can break open. This can result in serious bleeding and, in some cases, death.

FDA became aware of cases of non-cirrhotic portal hypertension through adverse event reports submitted to FDA's Adverse Event Reporting System (AERS). Based on these reports, FDA has revised the didanosine drug label to include information about non-cirrhotic portal hypertension to help ensure the safe use of this drug.

FDA believes the clinical benefits of didanosine for certain patients with HIV continue to outweigh its potential risks. The decision to use this drug, however, must be made on an individual basis between the treating physician and the patient.

Additional Information for Patients
Didanosine is a prescription medication used along with other drugs to treat patients who are infected with HIV, the virus that causes AIDS.
Didanosine works by reducing the growth of HIV.It belongs to a class of medications called nucleoside analogues.
Didanosine helps your body maintain its supply of immune cells called CD4 cells. These cells are important for fighting HIV and other infections.
Non-cirrhotic portal hypertension is a serious, but rare, side effect that has occurred in patients using didanosine.

Additional Information for Healthcare Professionals
Be aware that didanosine use has been associated with the development of non-cirrhotic portal hypertension.
Discuss with patients the clinical benefits and potential risks, including the risk of non-cirrhotic portal hypertension, with the use of didanosine.
Continue to monitor patients for the development of portal hypertension and esophageal varices.
Be aware that didanosine already has a Boxed Warning for lactic acidosis and hepatomegaly with steatosis.
Didanosine in combination with other antiretroviral agents as well as hydroxyurea or ribavirin has been associated with the development of liver toxicity.

Data Summary
FDA's decision to revise the drug label for didanosine is based on post-marketing reports of patients developing non-cirrhotic portal hypertension while using didanosine. Other liver adverse events such as lactic acidosis, hepatomegaly with steatosis, and liver failure have been reported with the use of didanosine alone and in combination with other antiviral drugs.
Of the 42 post-marketing cases of non-cirrhotic portal hypertension in patients using didanosine:
Twenty-six were males, 14 were females, and in two no gender was specified.
The ages ranged from 10 years to 66 years.
Duration of didanosine treatment ranged from months to years before development of non-cirrhotic portal hypertension.
Definitive cases of non-cirrhotic portal hypertension were confirmed by biopsy and had no alternative etiology for the diagnosis.
Medical interventions described in the reported cases included:
Banding/ligation of esophageal varices in 8 patients.
Transjugular intrahepatic portosystemic shunt (TIPSS) procedure in three patients.
Liver transplantation in 3 patients.
There were four deaths total in the 42 reported cases. The cause of death in the four patients was due to:
Hemorrhage from esophageal varices in two patients.
Progressive liver failure in one patient.
A combination of multi-organ failure, cerebral hemorrhage, sepsis, and lactic acidosis in one patient.

The only patients who have been reported as fully recovered are the three non-cirrhotic portal hypertension patients who received a liver transplant.

A causal association is difficult to determine from postmarketing reports alone. However, based on the number of well-documented cases and exclusion of other causes of portal hypertension such as alcohol-related cirrhosis or hepatitis C, FDA concludes there is an association between use of didanosine and development of non-cirrhotic portal hypertension. Because of the potential severity of portal hypertension, including death from hemorrhaging esophageal varices, FDA has revised the Warning and Precautions section of the didanosine drug label to assure safe use of the medication.

The Videx EC and Videx Pediatric Powder for Oral Solution were revised as follows:
In Highlights section of the package insert under Warnings and Precautions, the following was added:

Non-cirrhotic portal hypertension: Discontinue didanosine in patients with evidence of non-cirrhotic portal hypertension

In section 5 Warnings and Precautions the following new subsection was added:
5.4 Non-cirrhotic Portal Hypertension

Postmarketing cases of non-cirrhotic portal hypertension have been reported, including cases leading to liver transplantation or death. Cases of didanosine-associated non-cirrhotic portal hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis. Onset of signs and symptoms ranged from months to years after start of didanosine therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly. Patients receiving Videx should be monitored for early signs of portal hypertension (eg. Thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory testing including liver enzymes, serum bilirubin, albumin, complete blood count, and international normalized ratio (INR) and ultrasonography should be considered. Videx should be discontinued in patients with evidence of non-cirrhotic portal hypertension

In section 17 Patient Counseling Information the following was added:
17.5 Non-cirrhotic Portal Hypertension
Patients should be informed that non-cirrhotic portal hypertension has been reported in patients taking Videx, including cases leading to liver transplantation or death.
Videx and VidexEC are Nucleoside Reverse Transcriptase Inhibitors (NRTIs), products of Bristol Myers-Squibb.

Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

FDA Drug Safety Communication: Serious liver disorder associated with the use of Videx/Videx EC (didanosine)



FDA Drug Safety Communication: Serious liver disorder associated with the use of Videx/Videx EC (didanosine)

Safety Announcement
[01-29-2010] The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals and patients about a rare, but serious, complication in the liver known as non-cirrhotic portal hypertension in patients using Videx or Videx EC (didanosine). Didanosine is a medication used to treat human immunodeficiency virus (HIV) infection. Videx was the first approved didanosine medication. Videx EC is a delayed-release version of Videx.

Non-cirrhotic portal hypertension (portal hypertension that is not caused by cirrhosis of the liver) is rare in the United States. It occurs when blood flow in the major vein in the liver (the portal vein) slows down. This slowed blood flow can lead to the development of severely enlarged esophageal veins (varices) in the gastrointestinal system. Because esophageal varices are thin and portal hypertension increases the pressure of blood flow in these veins, esophageal varices can break open. This can result in serious bleeding and, in some cases, death.

FDA became aware of cases of non-cirrhotic portal hypertension through adverse event reports submitted to FDA's Adverse Event Reporting System (AERS). Based on these reports, FDA has revised the didanosine drug label to include information about non-cirrhotic portal hypertension to help ensure the safe use of this drug.

FDA believes the clinical benefits of didanosine for certain patients with HIV continue to outweigh its potential risks. The decision to use this drug, however, must be made on an individual basis between the treating physician and the patient.



Additional Information for Patients
Didanosine is a prescription medication used along with other drugs to treat patients who are infected with HIV, the virus that causes AIDS.
Didanosine works by reducing the growth of HIV.It belongs to a class of medications called nucleoside analogues.
Didanosine helps your body maintain its supply of immune cells called CD4 cells. These cells are important for fighting HIV and other infections.
Non-cirrhotic portal hypertension is a serious, but rare, side effect that has occurred in patients using didanosine.


Additional Information for Healthcare Professionals
Be aware that didanosine use has been associated with the development of non-cirrhotic portal hypertension.
Discuss with patients the clinical benefits and potential risks, including the risk of non-cirrhotic portal hypertension, with the use of didanosine.
Continue to monitor patients for the development of portal hypertension and esophageal varices.
Be aware that didanosine already has a Boxed Warning for lactic acidosis and hepatomegaly with steatosis.
Didanosine in combination with other antiretroviral agents as well as hydroxyurea or ribavirin has been associated with the development of liver toxicity.


Data Summary
FDA's decision to revise the drug label for didanosine is based on post-marketing reports of patients developing non-cirrhotic portal hypertension while using didanosine. Other liver adverse events such as lactic acidosis, hepatomegaly with steatosis, and liver failure have been reported with the use of didanosine alone and in combination with other antiviral drugs.

Of the 42 post-marketing cases of non-cirrhotic portal hypertension in patients using didanosine:

Twenty-six were males, 14 were females, and in two no gender was specified.
The ages ranged from 10 years to 66 years.
Duration of didanosine treatment ranged from months to years before development of non-cirrhotic portal hypertension.
Definitive cases of non-cirrhotic portal hypertension were confirmed by biopsy and had no alternative etiology for the diagnosis.
Medical interventions described in the reported cases included:

Banding/ligation of esophageal varices in 8 patients.
Transjugular intrahepatic portosystemic shunt (TIPSS) procedure in three patients.
Liver transplantation in 3 patients.
There were four deaths total in the 42 reported cases. The cause of death in the four patients was due to:

Hemorrhage from esophageal varices in two patients.
Progressive liver failure in one patient.
A combination of multi-organ failure, cerebral hemorrhage, sepsis, and lactic acidosis in one patient.
The only patients who have been reported as fully recovered are the three non-cirrhotic portal hypertension patients who received a liver transplant.

A causal association is difficult to determine from postmarketing reports alone. However, based on the number of well-documented cases and exclusion of other causes of portal hypertension such as alcohol-related cirrhosis or hepatitis C, FDA concludes there is an association between use of didanosine and development of non-cirrhotic portal hypertension. Because of the potential severity of portal hypertension, including death from hemorrhaging esophageal varices, FDA has revised the Warning and Precautions section of the didanosine drug label to assure safe use of the medication.

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FDA Drug Safety Communication: Serious liver disorder associated with the use of Videx/Videx EC (didanosine)