Tamiflu (Oseltamivir)

What is Tamiflu - Oseltamivir?

Oseltamivir (INN) (Tamiflu) is an antiviral drug that slows the spread of influenza (flu) virus between cells in the body by stopping the virus from chemically cutting ties with its host cell—median time to symptom alleviation is reduced by 0.5–1 day. The drug is sold under the trade name Tamiflu and is taken orally in capsules or as a suspension. It has been used to treat and prevent Influenzavirus A and Influenzavirus B infection in over 50 million people since 1999.

Oseltamivir is a prodrug, a (relatively) inactive chemical which is converted into its active form by metabolic process after it is taken into the body. It was the first ''orally active'' neuraminidase inhibitor commercially developed. It was developed by C.U. Kim, W. Lew and X. Chen of US based Gilead Sciences and is currently marketed by Hoffmann–La Roche (Roche). In Japan, it is marketed by Chugai Pharmaceutical Co., which is more than 50% owned by Roche.

The World Health Organization (WHO) reported 264 out of over 15,000 samples of the prevalent 2009 pandemic H1N1 (swine) flu tested worldwide have shown resistance to oseltamivir, contrasting sharply with the 99.6% of the seasonal H1N1 flu strains tested which have resistance to oseltamivir.

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Tamiflu - Oseltamivir Clinical Usage

Mechanism of action

The drug Oseltamivir is itself not virally effective; however, once in the liver, it is converted by natural chemical processes, hydrolysed hepatically to its active metabolite, the free carboxylate of oseltamivir (GS4071). The usual adult dosage for treatment of influenza is 75 mg twice daily for 5 days, beginning within 2 days of the appearance of symptoms and with decreased doses for children and patients with renal impairment. Oseltamivir may be given as a preventive measure either during a community outbreak or following close contact with an infected individual. Standard prophylactic dosage is 75 mg once daily for patients aged 13 and older, which has been shown to be safe and effective for up to six weeks. The importance of early treatment is that the NA protein inhibition is more effective within the first 48 hours. If the virus has replicated and infected many cells the effectiveness of this medication will be severely diminished, especially over time.

The Centers for Disease Control and Prevention (CDC) recommends physicians prioritize which patients they prescribe oseltamivir to. Specifically, people hospitalized with more severe illness, children younger than 2 years old, adults over 65, pregnant women, people with certain chronic medical or immunosuppressive conditions and adults under 19 on long-term aspirin therapy. However, they also advise that children and adults presenting with suspected flu that have symptoms of lower respiratory tract illness or clinical deterioration should also receive prompt empiric antiviral therapy, regardless of previous health or age.

The standard recommended dose incompletely suppresses viral replication in at least some patients with H5N1 avian influenza, increasing the risk of viral resistance and rendering therapy less effective. Accordingly, it has been suggested that higher doses and longer durations of therapy should be used for treatment of patients with the H5N1 virus.

Clinical trials for an increased dosage began in May 2007. All avian influenza cases in Indonesia, Thailand, and Vietnam were inducted into the trial. The trial also included 100 cases of severe seasonal influenza from each of those countries and the United States. Half received the current standard dose, and half received a double dose, but for the standard length of time.

Efficacy

On December 8 the Cochrane Collaboration, which reviews medical evidence, announced in a review published in the British Medical Journal that it had reversed its previous findings that the antiviral drug Tamiflu can ward off pneumonia and other serious conditions linked to influenza. They reported that an analysis of 20 studies showed Tamiflu offered mild benefits for healthy adults if taken within 24 hours of onset of symptoms, but found no clear evidence it prevented lower respiratory tract infections or other complications of influenza. Their published finding relates only to its use in healthy adults with influenza; they say nothing about its use in patients judged to be at high risk of complications—pregnant women, children under 5, and those with underlying medical conditions, and uncertainty over its role in reducing complications in healthy adults may still leave it as a useful drug for reducing the duration of symptoms.

Co-administration with probenecid

It has been suggested that co-administration of oseltamivir with probenecid could extend a limited supply of oseltamivir. Probenecid reduces renal excretion of the active metabolite of oseltamivir. One study showed that 500 mg of probenecid given every six hours doubled both the peak plasma concentration (Cmax) and the half-life of oseltamivir, increasing overall systemic exposure (AUC) by 150 percent. Although the evidence for this interaction comes from a study by Roche, it was publicised only in October 2005 by a doctor who had reviewed the data. Probenecid was used in similar fashion during World War II to extend limited supplies of penicillin. It is still used to increase penicillin concentrations in serious infections.

Possible side effects

Common adverse drug reactions (ADRs) associated with oseltamivir therapy (occurring in over 1% of clinical trial participants) include: nausea, vomiting, diarrhea, abdominal pain, and headache. Rare ADRs include: hepatitis and elevated liver enzymes, rash, allergic reactions including anaphylaxis, and Stevens-Johnson syndrome. This stems from cases in Japan, where the drug is most heavily prescribed, consuming 60% of the world's production. Concern has focused on teenagers, but problems have also been reported in children and adults.

In March 2007, Japan's Health Ministry warned that oseltamivir should not be given to those aged 10 to 19. The Ministry had previously decided, in May 2004, to change the literature accompanying oseltamivir to include neurological and psychological disorders as possible adverse effects, including: impaired consciousness, abnormal behavior, and hallucinations. A renewed investigation of the Japanese data was completed in April 2007. It found that 128 patients had been reported to behave abnormally after taking oseltamivir since 2001. Forty-three of them were under 10 years old, 57 patients were aged 10 to 19, and 28 patients were aged 20 or over. Eight people, including five teens and three adults, had died from these actions.

To determine whether to lift the 2007 ban, a research team from the Japanese Health, Labour and Welfare Ministry studied 10,000 children under the age of 18 who had been diagnosed with influenza since 2006. The study was finalised in April 2009. Taking into account all degrees of abnormal behaviour, including minor behavioural problems such as incoherent speech, the study found that children who took oseltamivir were 54 percent more likely to exhibit abnormal behaviour than those who did not take the drug. When the team limited its analysis to children who had displayed serious abnormal behaviour that led to injury or death, it found those who had taken oseltamivir were 25 per cent more likely to behave unusually.

In November 2006, the United States Food and Drug Administration (FDA) amended the warning label to include the possible side effects of delirium, hallucinations, or other related behavior. This went further than the FDA's previous pronouncement, from a year before, that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two were from neurological problems, although more have died since then). The change to a more cautionary stance was attributed to 103 new reports that the FDA received of delirium, hallucinations and other unusual psychiatric behavior, mostly involving Japanese patients, received between August 29, 2005 and July 6, 2006. This was an increase from the 126 similar cases logged between the drug's approval in 1999 and August 2005.

Roche points out that oseltamivir has been used to treat over 50 million people since 1999, and states that influenza may itself cause psychological problems.

In March 2007, the European Medicines Agency said that the benefits of oseltamivir outweighed the costs, but that it would closely monitor reports from Japan.

In April 2007, South Korea issued a safety warning against prescribing oseltamivir to teenagers except in special cases.

A joint investigation by the British Medical Journal (BMJ) and British TV Channel 4 published in the BMJ on December 8, 2009 concluded that in otherwise healthy adults they "have no confidence in claims that oseltamivir reduces the risk of complications and hospital admission in people with influenza" and believe it should not be used in routine control of seasonal influenza. There was also concern about under-reporting of side effects of the drug. In contrast, according to the BMJ, Roche has stated in media briefings that oseltamivir reduced hospital admissions by 61%; secondary complications (including bronchitis, pneumonia, and sinusitis) by 67% in otherwise healthy individuals and lower respiratory tract infections requiring antibiotics by 55%.

BMJ editor Dr. Fiona Godlee, said "claims that oseltamivir reduces complications have been a key justification for promoting the drug's widespread use. Governments around the world have spent billions of pounds on a drug that the scientific community has found itself unable to judge."

There is evidence that oseltamivir has a modest effect in reducing some minor flu symptoms and contagiousness in otherwise healthy adults by about one day, but this is probably not the main reason most doctors are prescribing the drug for their patients. This less important benefit may well be offset by the risks of the drug.

Mutagenesis, cell transformation, impairment of fertility, and carcinogenesis

Although found to be non-mutagenic in the Ames test and the mouse micronucleus test, Tamiflu tested positive in the Syrian Hamster Embryo (SHE) cell transformation test.

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Tamiflu - Oseltamivir Resistance

Mutations conferring resistance are single amino acid residue substitutions (His274Tyr) in the neuraminidase enzyme.

Seasonal H1N1

According to the CDC, oseltamivir is not very effective in the 2008 seasonal H1N1 virus anymore due to acquired resistance in 99.6% of all 2008 seasonal H1N1 strains, up from 12% in 2007-2008 flu season.

H3N2

Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. First, children typically have a longer infection period, giving a longer time for resistance to develop. Second, Kiso ''et al.'' claim to have used more rigorous detection techniques than previous studies. According to the CDC, as of October 3, 2009 no influenza B strains tested have shown any resistance to oseltamivir.

H5N1 avian influenza

High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. She was being treated with oseltamivir at time of detection. de Jong ''et al.'' (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. They also note that the recommended dosage of oseltamivir does not always completely suppress viral replication, a situation that could favor the emergence of resistant strains. Moscona (2005) gives a good overview of the resistance issue, and says that personal stockpiles of oseltamivir could lead to under-dosage and thus the emergence of resistant strains of H5N1.

Resistance is of concern in the scenario of an influenza pandemic (Wong and Yuen 2005), and may be more likely to develop in avian influenza than seasonal influenza due to the potentially longer duration of infection by novel viruses. Kiso ''et al.'' suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic.

H5N1 has not yet been transmissible from person to person and is acquired by people working with or near infected poultry.

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Tamiflu - Oseltamivir Personal Stockpiling

A short supply of oseltamivir prompted some individuals to stockpile the drug. Several American states issued advisories strongly discouraging this practice. Production has since caught up with current demand.

In the ''New England Journal of Medicine'', Anne Moscona (2005) argues that the use of personal stockpiles of oseltamivir could result in the administration of low dosages, allowing for the development of drug-resistant virus strains.

A third argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. In December 2005, 53 packages of counterfeit Tamiflu tablets were intercepted by the US Customs Service in South San Francisco. The packages were labeled "Generic Tamiflu". Roche officials know of only one instance of counterfeit Tamiflu appearing outside of the United States: incorrectly-labelled tablets found in Holland, which contained only Vitamin C and lactose.

An argument in favor of individual stockpiling is that Roche is on the record as saying that without more orders, they may have to actually curtail production. Individual stockpiling could bring market forces to play, maintaining production capacity and allowing the total supply on hand to be higher in case demand again outstrips production in the future, for instance, during a sudden influenza outbreak.

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses material from the Wikipedia article on "Oseltamivir" All material adapted used from Wikipedia is available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.