New WHO guidelines recommend the phasing-out of the major HIV-drug Stavudine

November 30, 2009

November 29, 2009  – The World Health Organization (WHO) recently announced new recommendations (guidelines) on HIV-therapies worldwide.

An important part of this announcement concerns Stavudine.  Countries should phase out the use of Stavudine, the most widespread antiretroviral, because of “long-term, irreversible” side-effects in HIV patients including wasting and a nerve disorder, according to the WHO.

Stavudine [Zerit], also known as d4T, or as generic Stavudine in the market place, is a type of medicine called a nucleoside reverse transcriptase inhibitor (NRTI). This class of medicines blocks reverse transcriptase, a protein that HIV needs to make more copies of itself. According to the WHO, Stavudine is widely available in developing countries as a first-line therapy of the HIV-infection, is relatively cheap, and easy to use. But it causes a nerve disorder leading to numbness and burning pain in the hands and feet, and loss of body fat known as lipoatrophy or wasting, conditions that are disabling and disfiguring.

Of over 4 million people globally who take antiretrovirals, about half (50%) are still on a regimen containing Stavudine, down from 80 percent in 2006 when the WHO first said countries should envisage moving away from it because of its long-term effects.

Less toxic alternatives

The WHO recommends that countries progressively phase out the use of Stavudine as a preferred first-line therapy option and move to less toxic alternatives such as Zidovudine [Retrovir], also known as AZT ZDV, or generic Zidovudine in the marketplace, or TDF Tenofovir [Viread], also known as TDF. These are thought to be equally effective alternatives, according to WHO.

In another considerable change to its existing guidelines, the WHO also recommends that people with HIV, including pregnant women, should start taking antiretroviral drugs earlier to live a longer and healthier life. For the first time it advised HIV-positive women and their babies to take the drugs while breastfeeding to prevent mother-to-child transmission of the virus that causes AIDS.

An earlier start to treatment of HIV-infected adults and adolescents with antiretrovirals reduces their viral load much sooner and therefore also lowers the risk of them spreading the virus, according to the WHO. The new recommendations are based on a solid body of evidence indicating that rates of death, morbidity and HIV and tuberculosis transmissions are all reduced by starting treatment earlier.

This approach is thought to prolong and improve the quality of life of enormous numbers of patients, WHO states. Accoring  to the recent annual UN report, an estimated 33.4 million people worldwide, two thirds of them in sub-Saharan Africa, are infected with the AIDS virus.

Mutant genes linked to Parkinson’s disease in some patients of Japanese or European descent

November 20, 2009

November 20, 2009 – Two independent studies which tried to uncover genetic associations behind Parkinson’s disease have been published in the latest issue of Nature Genetics. They are the largest studies of this type to date and involved more than 25’000 participants.

The two research teams have found that people of Japanese and European descent who have mutant versions of five genes may be at higher risk of developing Parkinson’s disease.

The first study in Japan looked at ethnic Japanese  only while the second study, performed in the United States, focused on people of European heritage only.

Thus, in the first study, researchers at the Kobe University in Japan and sequenced the genes of 2’011 participating patients with Parkinson’s disease and 18’381 other study participants without the disease. They found that those with the disease were carriers of genetic variants of the PARK16, BST1, SNCA and LRRK2 genes. In the second study, researchers at the National Institutes of Health’s (NIH) Laboratory of Neurogenetics in the US analyzed the genes of more than 5’000 patients of European ancestry who suffer from the disease and detected strong links between Parkinson’s and genetic variants of the genes SNCA and MAPT. The two teams later compared their data and found that variants of PARK16, SNCA and LRRK2 carry risk of Parkinson’s disease in both Japanese and European populations, while genetic variants of BST1 and MAPT, repectively, seemed to specific for patients of Japanese or European descent.

The researchers hope that the better understanding of the underlying genetic variants involved in the progress of Parkinson’s disease will lead to better insights into the causes and underlying biology of this disease. Eventually, this knowledge will one day provide physicians with strategies to delay, or even prevent, the development of Parkinson’s disease.

Parkinson’s disease is a neurodegenerative disease that affects one to two percent of people over the age of 65. It is characterized by tremors, sluggish movement, muscle stiffness, and difficulty with balance. Although medical treatments today may improve symptoms, there are none that can slow down or halt the progression of the disease.

Avoid Coadministration of Clopidogrel [Plavix] and Omeprazole [Prilosec] or Esomeprazole [Nexium]

November 18, 2009

November 17, 2009 – Today, the US Food and Drug Administration (FDA) informed on new data showing that the proton pump inhibitor (PPI) Omeprazole [Prilosec] or [Prilosec OTC] reduces the anti-blood clotting effect of Clopidogrel [Plavix] by almost half when these 2 medicines are taken by the same patient. Patients at risk for heart attacks or strokes who use Clopidogrel [Plavix] to prevent blood clots will not get the full effect of this medicine if they are also taking Omeprazole [Prilosec]; therefore, the FDA recommends that the coadministration of Omeprazole [Prilosec] and Clopidogrel [Plavix] be avoided.

The new recommendations, updated from a January 2009 Early Communication, are based on study results from the manufacturers of Clopidogrel [Plavix]. The studies confirm that coadministration of Omeprazole [Prilosec] with Clopidogrel [Plavix] results in decreased levels of Clopidogrel [Plavix]’s active metabolite, reducing Clopidogrel [Plavix]’s anticlotting effect.

Omeprazole [Prilosec] inhibits the drug-metabolising enzyme CYP2C19, which is responsible for the conversion of Clopidogrel [Plavix] into its active metabolite with anticlotting activity. The new studies compared the amount of Clopidogrel [Plavix]’s active metabolite in the blood and its effect on platelets in patients who took Clopidogrel [Plavix] plus Omeprazole [Prilosec] versus those who took Clopidogrel [Plavix] alone. A reduction in active metabolite levels of about 45% was found in those who received Clopidogrel [Plavix] with Omeprazole [Prilosec] compared with those taking Clopidogrel [Plavix] alone. The effect of Clopidogrel [Plavix] on platelets was reduced by as much as 47% in patients receiving Clopidogrel [Plavix] and Omeprazole [Prilosec] together. These reductions were seen whether the drugs were given at the same time or 12 hours apart.

Since the level of inhibition among other PPIs varies, it is unknown to what amount other PPIs may interfere with Clopidogrel [Plavix]. However, Esomeprazole [Nexium], a PPI that is the S-enantiomer of omeprazole and as such also contained in Omeprazole [Prilosec], inhibits CYP2C19 and should also be avoided in combination with Clopidogrel [Plavix].

Other stomach acid-reducing drugs, such as Ranitidine [Zantac], Famotidine [Pepcid], Nizatidine [Axid], or antacids, are not expected to interfere with the anticlotting activity of Clopidogrel [Plavix] because they do not inhibit CYP2C19 enzyme activity. However, Cimetidine [Tagamet] or [Tagamet HB] does inhibit CYP2C19 activity and should also not be used together with Clopidogrel [Plavix].

In addition to Cimetidine [Tagamet], other drugs that are potent inhibitors of the CYP2C19 enzyme would be expected to have a similar effect and should be avoided in combination with Clopidogrel [Plavix]. These include Fluconazole [Diflucan], Ketoconazole [Nizoral], Voriconazole [VFEND], Etravirine [Intelence], Felbamate [Felbatol], Fluoxetine, as [Prozac], [Sarafem], or  [Symbyax], Fluvoxamine [Luvox], and Ticlopidine [Ticlid].

Sanofi-aventis and Bristol-Myers Squibb, the makers of Plavix (Clopidogrel [Plavix]), are updating this drug’s label with the details of the studies and are conducting follow-up studies to further explore drug interactions with Clopidogrel [Plavix].

Until further information is available, FDA recommends the following:

• The concomitant use of Omeprazole [Prilosec] and Clopidogrel [Plavix] should be avoided because of the effect on Clopidogrel [Plavix]’s active metabolite levels and anticlotting activity. Patients at risk for heart attacks or strokes, who are given Clopidogrel [Plavix] to prevent blood clots, may not get the full protective anticlotting effect if they also take prescription drug Omeprazole [Prilosec] or Omeprazole [Prilosec OTC], its over the counter (OTC) form.

• Separating the dose of Clopidogrel [Plavix] and Omeprazole [Prilosec] in time will not reduce this drug interaction.

• Other drugs that should be avoided in combination with Clopidogrel [Plavix] because they may have a similar interaction include Esomeprazole [Nexium],  Cimetidine [Tagamet], Fluconazole [Diflucan], Ketoconazole [Nizoral], Voriconazole [VFEND], Etravirine [Intelence], Felbamate [Felbatol], Fluoxetine, as [Prozac], [Sarafem], or  [Symbyax], Fluvoxamine [Luvox], and Ticlopidine [Ticlid].

• At this time the FDA does not have sufficient information about drug interactions between Clopidogrel [Plavix] and PPIs other than Omeprazole [Prilosec] and Esomeprazole [Nexium] to make specific recommendations about their coadministration. Healthcare professionals and patients should consider all treatment options carefully before beginning therapy.

• There is no evidence that other drugs that reduce stomach acid, such as most H2 blockers Ranitidine [Zantac], Famotidine [Pepcid], Nizatidine [Axid] (except Cimetidine [Tagamet] or [Tagamet HB], which is potent CYP2C19 enzyme inhibitor), or antacids interfere with the anticlotting activity of Clopidogrel [Plavix]. Ranitidine and Famotidine are available by prescription and OTC to relieve and prevent heartburn and antacids are available OTC to relieve heartburn.

• Talk with your patients about the OTC medicines they take. Be aware that patients may be taking nonprescription forms of Omeprazole [Prilosec] and Cimetidine [Tagamet]. Likewise, patients are urged to inform their physicians if they take any of these OTC medicines.

The FDA will continue to investigate other drug interactions with Clopidogrel [Plavix]. The FDA plans on presenting this issue at the next meeting of the FDA’s Drug Safety Oversight Board in November. The Agency will communicate any further recommendations or conclusions once additional information is available.

Phamacogenetic considerations (added by the blog author)

Patients should be aware that even without taking any of the aforementioned  CYP2C19 enzyme-inhibiting co-medications, monozygote carriers of the loss of function CYP2C19*2, CYP2C19*3,  CYP2C19*4, and CYP2C19*5 allelic variants may experience a considerably reduced transformation of Clopidogrel [Plavix] to its pharmacologically active metabolite responsible for the anti-clotting activity. This may also be true for patients who are compound heterozygote carriers of such alleles, for example  CYP2C19*2/CYP2C19*3, etc. More information on this aspect can be found here and here.

European Medicines Agency (EMEA) Pandemic Influenza (H1N1) Portal: Celvapan Approved

November 7, 2009

November 7, 2007 – According to the Pandemic Influenza (H1N1) Portal by the European Medicines Agency (EMEA), Celvapan has recently been approved.

Celvapan is a vaccine that is given by injection into the shoulder muscle in two doses, at least three weeks apart. It contains influenza (flu) viruses that have been inactivated (killed). Celvapan contains a flu strain called A/California/07/2009 (H1N1)v. Celvapan is intended to protect against ‘pandemic’ flu. It should only be used for the influenza A (H1N1) pandemic that was officially declared by the World Health Organization on 11 June 2009. A flu pandemic happens when a new strain of flu virus appears that can spread easily from person to person because people have no immunity (protection) against it. A pandemic can affect most countries and regions around the world. Celvapan is given according to official recommendations. The vaccine can only be obtained with a prescription.

As a vaccine, Celvapan works by ‘teaching’ the immune system (the body’s natural defences) how to defend itself against a disease. Celvapan contains a virus called A(H1N1)v that is causing the current pandemic. The virus has been inactivated so that it does not cause any disease. When a person is given the vaccine, the immune system recognises the inactivated virus as ‘foreign’ and makes antibodies against it. The immune system will then be able to produce antibodies more quickly when it is exposed to the virus again. This helps to protect against the disease. The viruses used in Celvapan are grown in mammal cells (‘vero cells’), unlike those in some other flu vaccines, which are grown in hen’s eggs.

Celvapan was first developed as a ‘mock-up’ vaccine that contained an H5N1 strain of the flu virus called A/Vietnam/1203/2004. The company studied the ability of this mock-up vaccine to trigger the production of antibodies (‘immunogenicity’) against this strain of flu virus in advance of the pandemic. Following the start of the current pandemic, the company replaced the virus strain in Celvapan with the H1N1 strain causing the pandemic, and presented data relating to this change to the Committee for Medicinal Products for Human Use (CHMP).

The mock-up vaccine was shown to bring about protective levels of antibodies in at least 70% of the people in which it was studied. In line with the criteria laid down by the CHMP, this demonstrated that the vaccine brought about an appropriate level of protection. The CHMP was also satisfied that the change of strain to the H1N1 strain did not affect the characteristics of the vaccine.

Side effects

The most common side effect with Celvapan (seen in more than 1 people vaccinated in 10) is pain at the site of the injection. For the full list of all side effects reported with Celvapan, see the Package Leaflet. Celvapan should not be given to people who have had an anaphylactic reaction (severe allergic reaction) to any of the components of the vaccine, or to any of the substances found at trace (very low) levels in the vaccine, such as formaldehyde, benzonase or sucrose.

However, it may be appropriate to give the vaccine to these patients during a pandemic, as long as facilities for resuscitation are available.

Why has Celvapan been approved

The CHMP decided that, based on the information obtained with the mock-up vaccine and the information provided on the strain change, the benefits of Celvapan are greater than its risks for the prophylaxis of influenza in the officially declared H1N1 pandemic situation. The Committee recommended that Celvapan be given marketing authorisation.

Celvapan has been authorised under ‘Exceptional Circumstances’. This means that it has not yet been possible to obtain full information about the pandemic vaccine. Every year, the European Medicines Agency will review any new information that may become available and this summary will be updated as necessary.

What information is still awaited for Celvapan

The company that makes Celvapan will collect information on the safety and effectiveness of the vaccine, and submit this to the CHMP for evaluation. The company that makes Celvapan will collect information on the safety of the vaccine while it is being used. This will include information on its side effects and its safety in children, the elderly, pregnant women, patients with severe conditions and people who have problems with their immune systems.

Other information about Celvapan

The European Commission granted a marketing authorisation valid throughout the EU for the H5N1 mock-up vaccine for Celvapan on 4 March 2009. The change to the marketing authorisation for the H1N1 virus was authorised by the European Commission on 6 October 2009. The full assessment report will be published shortly.

Please contact the Pandemic Influenza (H1N1) Portal by EMEA on similar information for two other vaccines approved: Focetria and Pandemrix.

Boxed Warning Updated: TNF Blockers and Cancer Risks in Children

November 3, 2009

November 3, 2009 – As we learn from it’s todays announcement, FDA is requiring stronger warnings about an increased risk of lymphoma and other cancers in children and adolescents who are treated with drugs that block tumor necrosis factor. TNF blockers include Infliximab [Remicade], Etanercept [Enbrel], Adalizumab [Humira], Certolizumab [Cimzia], and Golimumab [Simponi]. These drugs are used to treat juvenile rheumatoid arthritis, Crohn’s disease, and other inflammatory diseases.

The warnings, which include an updated boxed warning, are based on an FDA analysis of reports of cancer that occurred in children and adolescents treated with TNF-blockers. The cancers, some of which were fatal, occurred after an average of 30 months of treatment. About half of the cancers were lymphomas. The labeling will also include updated information on cases of leukemia and new onset psoriasis associated with TNF-blockers.

Healthcare professionals should monitor patients for development of malignancies during and after treatment with TNF blockers. They should also talk to patients and their families about this risk and tell them to report signs and symptoms of cancer such as unexplained weight loss or fatigue, easy bruising or bleeding, or swollen lymph nodes in the neck, underarms or groin.

Patients should also be monitored for signs or symptoms of new onset psoriasis or worsening psoriasis. The patient Medication Guide will be updated with this new information.

Additional Information: FDA MedWatch Safety Alert. Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi). August 4, 2009.

Considerable stroke risk linked to anemia drug; Darbepoetin-α [Aranesp] nearly doubled risk in people with diabetes

November 1, 2009

November 1, 2009 – A new study raises fresh safety concerns about widely used anemia medicines, finding that the drug Darbepoetin-α [Aranesp] nearly doubled the risk of stroke in people with diabetes and chronic kidney problems who are not yet sick enough to need dialysis. The study is the largest ever of these blood-boosting drugs and the only one that compared them to a dummy treatment. The medicines have become blockbuster sellers because they lessen the need for transfusions, but their ability to prevent heart attacks, kidney failure or other problems have not been proven.

Over the last two years, the federal Food and Drug Administration has repeatedly strengthened warning labels not only on Darbepoetin-α [Aranesp] , but on the similar drug products Epoetin-α [Epogen] and Epoetin-α [Procrit] as concerns rose that they may worsen survival in certain cancer patients, especially at higher doses.

The new study tested Darbepoetin-α [Aranesp] in a different group of patients: 4,038 people with Type 2 diabetes, kidney problems and moderate anemia  problems that often go hand in hand. The goal was to see if the drug could prevent heart attacks, heart failure, strokes or the need for dialysis. The leader of the study, Dr. M. Pfeffer, noted that the study did not only fail to do that, but a susbstantial  hightened risk for stroke was uncovered.  Strokes occurred in 101 patients given Aranesp and 53 patients given dummy shots. Looked at another way, the risk of suffering a stroke was about 1 percent per year in the placebo group and about 2 percent in those given Aranesp. Results were published online Friday by the New England Journal of Medicine (NEJM). For many patients, this risk will outweigh its potential benefits, the study’s authors concluded.

On a positive note, in the present study, Darbepoetin-α [Aranesp] did reduce the need for transfusions;  297 people on the drug needed them versus 496 of those getting dummy shots. However, there was only a modest improvement in how fatigued people said they felt in the Aranesp group.

For your convenience, you find the abstract of the study be Pfeffer M.A., et al., published at October 30, 2009 (10.1056/NEJMoa0907845). Please read the full study result at the link provided.

Background Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested.

Methods In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.

Results Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.

Conclusions The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. ( number, NCT00093015 [] .)

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