Oseltamivir (Tamiflu) For Influenza

Clinical Use

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Oseltamivir or more popularly known as Tamiflu is an antiviral medication that works by blocking the actions of influenza virus A and B in the body. Oseltamivir is used for the treatment of influenza in people who are one year old or more. This medicine is not used for the treatment of common cold. The drug is administered orally and it readily gets absorbed from the gastrointestinal tract after which it is converted from hepatic esterases to oseltamivir carboxylate [1].

The oseltamivir acts as an inhibitor of the neuraminidase enzyme which is expressed on the surface of the virus. This enzyme helps the virus by promoting its release from the infected cells to the respiratory tract. When oseltamivir inhibits this enzyme then virions are unable to move and remain attached to the membrane of the infected cells and also get entrapped in the respiratory secretions [2]. 

Zanamivir is used as an alternative to Oseltamivir for the treatment of influenza. Zanamivir is an inhaled drug and blocks the action of neuraminidase that helps the virus to spread from the infected cells to the healthy cells in the body. Hence this reduces the symptoms and duration of the influenza infection [3].

Both Zanamivir and oseltamivir have equal efficacy in the terms of reducing the symptoms of influenza. Both the medicines are prescribed to be given twice a day for five days. However oseltamivir is generally prescribed for the people at least of age 1 or older whereas Zanamivir is prescribed for people aging 7 years or more [4].

Oseltamivir has been found to be effective only against influenza A (H3N2) infection and is less effective against influenza B infection. It is also not much effective against H1NI viral infection whereas Zanamivir has been found to be effective against both influenza A and influenza B infection. Both the drugs are however have been found to be less effective against influenza A (H1N1) infection [5]. Both the drugs are neuraminidase inhibitors but the effectiveness of each drug is based upon the susceptibility of the influenza virus to the drug. Form researches it has been found that the influenza virus A and B are more susceptible to Oseltamivir than to Zanamivir. Moreover Zanamivir cannot be prescribed to a person who is allergic to milk protein or lactose. It should be avoided by pregnant woman or mothers giving breast feed to their child. It should also not be administered to person having heart or any kind of breathing problems such as asthma or chronic obstructive pulmonary disease. People suffering from mental illness should not be given Zanamivir[6].

Although Oseltamivir is widely used for the treatment of influenza but it has several side effects. Nausea and vomiting are the most common side effects. Apart from this frequent mood swings is more prevailed among children that consist of confusion in understanding simple things, agitation and self-injuries. Allergic reaction is also one of the side effects which consist of itching, rashes and breathing problems. The rare symptoms that have been reported so far consist of abdominal cramps, extreme back or arm pain, bloating, discomfort in the chest, diarrhea often accompanied by blood discharge, drooling, swelling on the face, increase in the heart beat, hoarseness, frequent thirst, shortness of breath and sudden weight loss[7].

Mode of action

Side effects associated with Zanamivir consist of mild to severe allergies such as shortness of breath, facial swellings, swelling of throat and lips. More common side effects caused by Zanamivir consist of headache, dizziness, vomiting, fever, body pain and symptoms of cold such as sneezing, stuffy nose and sore throat. In some rare cases Zanamivir causes articular rheumatism, hallucinations, loss of appetite and acute renal failure[8].

Oseltamivir is contraindicated in the patients having hypersensitivity to any of the components of the drug or to other food allergies such as allergy to lactose or milk proteins. The most adverse effect of this drug among adults is vomiting, headache, insomnia and nausea. Oseltamivir is strictly not prescribed for children below the age of 1 year old and the standardized dose of the drug is 3mg/Kg administered for five days. However vomiting, diarrhea and diaper rashes are common in effect among the children aging 1 year administered with oseltamivir[9]. 

The adult and adolescent dosage of Tamiflu is 75 mg twice daily taken for 5 days. If oral tablet cannot be swallowed by the patients, 12.5 ml of Tamiflu must be taken which delivers 75 mg of Tamiflu. For patient of two years to twelve years of age the dosage vary from 30 mg to 75 mg[10]. The dosage depends upon body weight. In case of babies less than 1 year of age ranging from 2 weeks to one year of age, 3mg/kg twice daily is the recommended dosage. If it is given in form of oral suspension, then it must be 0.5 ml/kg of the solution[11]. In case of renal impairments dosage adjustments are required where the creatinine clearance timing is 10-60 ml/min and patient suffering from end stage renal disease. If patient is receiving haemodialysis and continuous peritoneal dialysis it demands a dose adjustment. In case of patients who are suffering from end stage renal disease but not receiving any dialysis treatment, in such cases Tamiflu is not recommended. For patients of renal impairment having a creatinine clearance rate of >60-90 ml/min 75 mg of Tamiflu is recommended once daily. In case of >30-60 ml/min, 30 mg once daily is the recommended dosage. In case of >10-30 ml/min 30 mg is recommended at every alternate day. In case of end stage renal disease on haemodialysis and creatinine clearance of <10ml/min 30 mg of Tamiflu is recommended after every alternate haemodialysis cycle. In case of peritoneal dialysis patients where creatinine clearance is <10ml/min 30 mg of Tamiflu is recommended once a week immediately after the dialysis. In case of mild or moderate heaptic impairment no dosage adjustment is required[12].

The stability of Tamiflu and different forms of formulations are based upon empirical studies carried out as US FDA guidelines. Tamiflu is available in tablet format at different concentrations such as 30 mg, 45 mg or 75 mg. It is also available in oral suspension form with a concentration of 6 mg per ml. If the oral suspension is constituted, then this must be used within 17 days of preparation and within 10 days if it is stored under refrigerated condition. In case of emergency compounded suspension, the suspension must be kept under refrigeration for 5 weeks (35 days) at a temperature range of 2-8 degree centigrade. If it has to be kept at room temperature it can be kept for 5 days at 25 degree centigrade. All the storage conditions are based upon the stability studies carried out as per US FDA guidelines with glass and PET bottles. The oral suspensions can differ in dosages and can be made as per patient requirement. The simplicity and convenient dosing of Tamiflu make it the preferred one against other formulations. Patients are usually given dosage of 30 mg, 45 mg, 60 mg and 75 mg twice[13].

Alternative to Oseltamivir

From the above discussions it is evident Oseltamivir is the preferred medication against influenza virus as compared to other alternatives available to counteract influenza virus. The first reason behind preference of Oseltamivir against other medications is it has been approved by FDA and has been used during influenza season of 2014-2015 in USA. The FDA approval of Oseltamivir indicates its safety and efficacy are well studied before its clinical applications. Oseltamivir is a neuraminidase inhibitor which can inhibit both influenza virus A and B which justifies its usage in clinical aspect. The rivalry class of drugs such as amantadine and rimantadine are also used against influenza virus, but the high level of resistance of viral organisms suggests Oseltamivir to be used as first line of choice against influenza virus. Although amantadine is well tolerated due to widespread resistance it is no more recommended by clinicians. The resistance is usually seen in 2-4 days of treatment evident from amino acid substitution in M₂ proteins. Similarly with rimantadine the neurologic adverse effects are less, yet it is not recommended clinically due to its well resistance by the organisms. Since Oseltamivir can be used for children under less than one year, and also for adults it is the preferred choice by clinicians. It reaches peak serum concentration by 1 hour. Similarly, it is excreted effectively i.e.99% active Oseltamivir carboxylate through renal pathway. Tamiflu is available in pill form as well as liquid dosage, making it preferred choice over other rivalry such as Zanamivir which is not indicated for COPD and asthma patients. Rapivab is taken intravenously limiting its self-use by the patients. Zanamivir is used for treatment in patients of 7 years or older and for prevention it can be used for 5 years older or more. Peramivir is used only for adults of 18 years age or older. These limitations of counterparts and alternatives of Tamiflu make it the preferred one against others.

References

1. Shobugawa, Y., Saito, R., Sato, I., Kawashima, T., Dapat, C., Dapat, I. C., ... & Suzuki, H. Clinical effectiveness of neuraminidase inhibitors—oseltamivir, zanamivir, laninamivir, and peramivir—for treatment of influenza A (H3N2) and A (H1N1) pdm09 infection: an observational study in the 2010–2011 influenza season in Japan. Journal of Infection and Chemotherapy, 2012. 18(6), 858-864.

2. Kim, J. H., Resende, R., Wennekes, T., Chen, H. M., Bance, N., Buchini, S., ... & Withers, S. G. Mechanism-based covalent neuraminidase inhibitors with broad-spectrum influenza antiviral activity. Science, 2013.340(6128), 71-75.

3. Heneghan, C. J., Onakpoya, I., Thompson, M., Spencer, E. A., Jones, M., & Jefferson, T. Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ: British Medical Journal, 2014.348.

4. Kawai, N., Ikematsu, H., Iwaki, N., Maeda, T., Kanazawa, H., Kawashima, T., ... & Kashiwagi, S. A comparison of the effectiveness of zanamivir and oseltamivir for the treatment of influenza A and B. Journal of Infection, 2008.56(1), 51-57.

5. Meijer, A., Lackenby, A., Hungnes, O., Lina, B., Van Der Werf, S., Schweiger, B., ... & European Influenza Surveillance Scheme.Oseltamivir-resistant influenza virus A (H1N1), Europe, 2007–08 season. Emerging infectious diseases, 2009.15(4), 552.

6. Brillman, J. C. Try Zanamivir for Oseltamivir-Resistant Flu Virus.Emergency Medicine News, 2009.31(5), 8-17.

7. Strong, M., Burrows, J., Stedman, E., & Redgrave, P. Adverse drug effects following oseltamivir mass treatment and prophylaxis in a school outbreak of 2009 pandemic influenza A (H1N1) in June 2009, Sheffield, United Kingdom. Euro Surveill, 2010.15(19), 19565-19570.

8. Shun-Shin, M., Thompson, M., Heneghan, C., Perera, R., Harnden, A., & Mant, D. Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials.Bmj, 2009.339.

9. Tappenden, P., Jackson, R., Cooper, K., Rees, A., Simpson, E., Read, R., & Nicholson, K. G. Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation.2009

10. Kohno, S., Yen, M. Y., Cheong, H. J., Hirotsu, N., Ishida, T., Kadota, J. I., ... & Shimada, J. Phase III randomized, double-blind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection. Antimicrobial agents and chemotherapy, 2011.55(11), 5267-5276.

11. Cella, M., Knibbe, C., Danhof, M., & Della Pasqua, O.What is the right dose for children?. British journal of clinical pharmacology, 2010.70(4), 597-603.

12. Davies, B. E.. Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations. Journal of antimicrobial chemotherapy, 2010.65(suppl 2), ii5-ii10.

13. Gutiérrez-Mendoza, L. M., Schwartz, B., Lira, J. D. J. M. D., & Wirtz, V. J. Oseltamivir storage, distribution and dispensing following the 2009 H1N1 influenza outbreak in Mexico. Bulletin of the World Health Organization, 2012.90(10), 782-787.