Saturday, November 10, 2012

Study: Adverse Events Associated With Oseltamivir Outpatient Treatment



Photo Credit – Wikipedia


# 6709



Oseltamivir (aka Tamiflu ©) is an oral antiviral that was heavily stockpiled by many nations between 2005 and 2088 in anticipation of a  feared `bird flu’ pandemic. 


While that particular pathogen remains in the wings (sorry . . . I couldn’t help myself), a pandemic of porcine origin did emerged in 2009 (H1N1), and so these antivirals saw heavy use, particularly in Japan, Great Britain, and in the United States.


That said . . . the  stockpiling, and use, of Tamiflu has not been without some controversy.


Critics have pointed out a lack of Randomized Controlled Trials (RCTs) to gauge the effectiveness of the drug, and the BMJ has been working along with the Cochrane group to get the manufacturer, Hoffmann-La Roche, to release unpublished trial data.


Although falling short of the `gold standard’ RCTs preferred by the Cochrane group for inclusion in their analyses, we’ve seen a number of observational studies that suggest significant benefits from the drug.


In 2010 we saw an observational study that appeared in JAMA  (see Study: Antivirals Saved Lives Of Pregnant Women) that strongly suggested that Tamiflu was life saving for some patients with pandemic flu.


And again in 2010, in BMJ: Efficacy of Oseltamivir In Mild H1N1, we saw a study which suggested that the administration of oseltamivir may have significantly reduced the incidence of pneumonia among otherwise healthy pandemic H1N1 patients.


And lastly, in Study: Antiviral Therapy For H5N1, we saw the largest study to date on the outcomes of H5N1 patients who either received, or did not receive, antiviral treatment.


The research appears in the IDSA’s  Journal of Infectious Diseases. The bottom line is essentially out of 308 cases studied, the overall survival rate was a dismal 43.5%.


But . . . of those who received at least one dose of Tamiflu . . .  60% survived . . .  as opposed to only 24% who received no antivirals.


Efficacy arguments aside, there have also been concerns raised over possible side effects from the drug.


It is axiomatic that all drugs have side effects. In fact, in trials with placebos, test subjects have reported adverse reactions (nocebo effect) even though they were taking pills with no active ingredient.


Even the most widely used over-the-counter medications can – and sometimes do – cause serious adverse effects.


So the mere existence of adverse effects aren’t enough to counsel against a drug’s use. The risks of adverse effects must be weighed against the benefits the drug may provide.


Often these AEs are mild, and transitory, and of little concern.



But in 2006 we began to see reports out of Japan suggesting that a small number of adolescents taking Tamiflu had experienced serious neuropsychiatric symptoms, including delirium, hallucinations, and convulsions.


Whether these symptoms were produced by the drug, or by their viral infection, wasn’t known (see Study: Pediatric Neurological Complications With H1N1). But in November of 2006, the FDA posted this safety warning:


Tamiflu (oseltamivir phosphate)

Audience: Pediatric and primary care healthcare professionals and patients

[Posted 11/13/2006] Roche and FDA notified healthcare professionals of revisions to the PRECAUTIONS/Neuropsychiatric Events and Patient Information sections of the prescribing information for Tamiflu, indicated for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days and for the prophylaxis of influenza in patients 1 year and older.

There have been postmarketing reports (mostly from Japan) of self-injury and delirium with the use of Tamiflu in patients with influenza. People with the flu, particularly children, may be at an increased risk of self-injury and confusion shortly after taking Tamiflu and should be closely monitored for signs of unusual behavior. A healthcare professional should be contacted immediately if the patient taking Tamiflu shows any signs of unusual behavior.


During the 2009 pandemic millions of doses of Tamiflu were prescribed, often to children. While we heard reports of some adverse effects (primarily vomiting & nausea), serious reactions were rare. 


In 2010 we saw a review in the journal Eurosurveillance: Adverse Effects of Oseltamivir in Children, that looked at the antiviral treatment of a number of students at a primary school in Sheffield, UK during the 2009 pandemic. 


While none of the side effects reported were life-threatening, the nausea, vomiting, abdominal pain and other symptoms were bothersome enough that a minority of those who started the Tamiflu (< 10% ) stopped taking the drug.


Today we’ve a new, much larger study, that appears in the journal Pharmacoepidemiology and Drug Safety. It examines the risk of AEs (primarily psychiatric in nature) among more than 27,000 matched pairs (by sex, age, week of illness, and location - where half took the drug & half did not).


Encouragingly, they research concludes that `no evidence was identified for an increased risk of neuropsychiatric or other AEs following oseltamivir treatment.’

Original Report

Risk of adverse events following oseltamivir treatment in influenza outpatients, Vaccine Safety Datalink Project, 2007–2010†

Sharon K. Greene,, Lingling Li, David K. Shay, Alicia M. Fry, Grace M. Lee, Steven J. Jacobsen, Roger Baxter, Stephanie A. Irving, Michael L. Jackson, Allison L. Naleway, James D. Nordin, Komal J. Narwaney, Tracy A. Lieu

Article first published online: 5 NOV 2012


While comforting, this study doesn’t mean that oseltamivir is completely without side effects. Only that their research didn’t turn up an statistically significant increases in the AEs they were tracking among those taking the drug.


There are other concerns when it comes to use of oseltamivir, including the possibility that overuse will help generate resistant strains of the influenza virus.


But for now, oseltamivir remains one of the few pharmacological options we have available to treat severe influenza.

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