Introduction

Oseltamivir phosphate (Figure 1) is the prodrug converted by the liver to oseltamivir carboxylate, the active neuraminidase inhibitor. It works by preventing the viral neuraminidase required for infection and viral reproduction. This inhibition also prevents viral spread to respiratory secretions, thereby reducing respiratory infections. It is eliminated via the kidneys, and dosage adjustment is required for patients with a serum creatinine clearance of 10 to 30 mL/min.[1]

Indications

According to FDA prescribing information, oseltamivir phosphate is indicated for the treatment of acute, uncomplicated illness due to influenza A and B infection in patients 2 weeks of age and older who have been symptomatic for no more than 48 hours. In particular, this agent is indicated in adults and children including full-term neonates who present with symptoms typical of influenza when influenza virus is circulating in the community. Efficacy has been demonstrated when treatment is initiated within two days of the first onset of symptoms. Oseltamivir phosphate is also indicated for the prophylaxis of influenza in patients one year and older. Specifically, post-exposure prevention in individuals one year of age or older following contact with a clinically diagnosed influenza case when influenza virus is circulating in the community qualifies for such prophylactic therapy. Oseltamivir phosphate would only be indicated for post-exposure prevention of influenza in infants less than 1 year of age during a pandemic influenza outbreak.

According to the CDC,oseltamivir phosphate is not meant to replace the use of the influenza vaccine, which is the best way to protect against the flu. Oseltamivir phosphate should not be administered to patients two weeks prior or 48 hours after vaccination with live attenuated influenza vaccine . Oseltamivir phosphate has not been shown to affect the use of the trivalent inactivated influenza vaccine. There are no other clinically significant drug interactions with oseltamivir phosphate.[2]

Pharmacodynamics

There have been postmarketing reports of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving oseltamivir phosphate. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be uncommon based on oseltamivir phosphate. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of oseltamivir phosphate to these events has not been established. Influenza can be associated with a variety of neurologic and behavioral symptoms that can include events such as hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease.[3,4]

Mechanism of action

Oseltamivir phosphate is a pro-drug of the active metabolite (oseltamivir carboxylate) which is a potent and selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteins found on the virion surface. Viral neuraminidase enzyme activity is important for viral entry into uninfected cells, for the release of recently formed virus particles from infected cells, and for the further spread of the infectious virus in the body. Oseltamivir phosphate activity reduces viral shedding and infectivity. Oseltamivir phosphate is effective agaisnt viral neuraminidases of influenza A (including pandemic H1N1) and influenza B.

Absorption and Route of elimination

Oseltamivir phosphate is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is extensively converted by predominantly hepatic esterases to the active metabolite oseltamivir carboxylate. At least 75 % of an oral dose reaches the systemic circulation as the active metabolite. Exposure to the pro-drug is less than 5 % relative to the active metabolite. Plasma concentrations of both pro-drug and active metabolite are proportional to dose and are unaffected by co-administration with food.Pharmacokinetic parameters following twice daily dosing of oseltamivir phosphate 75mg capsules are as follows: Cmax of oseltamivir phosphate and oseltamivir carboxylate were found to be 65ng/mL and 348ng/mL, respectively, while AUC (0-12h) of oseltamivir phosphate and oseltamivir carboxylate were found to be 112ng·h/mL and 2719ng·h/mL, respectively.

Following absorption, oseltamivir phosphate is more than 90 % eliminated through conversion to oseltamivir carboxylate and subsequent elimination entirely through renal excretion. During clinical studies, less than 20 % of oral radiolabelled dose was found to be eliminated in faeces.

Adverse Reactions

Oseltamivir phosphate’s manufacturer disclosed study findings that report the most common adverse reactions in infants two weeks to less than one year are vomiting, diarrhea, and diaper rash.Health care providers should be cognizant of how common adverse reactions in older children can be manifested in infants. Children one to 12years of age may experience nausea and vomiting as the most common side effect, but epistaxis, conjunctivitis, ear disorder, and abdominal pain may also occur . Although noted in the older population, infants are not able to report certain side effects, such as nausea . Administering with food has not shown to have an effect on absorption, and food might lessen gastrointestinal irritability in some patients.[1]

Other more serious side effects have been reported, mostly from Japan, where use of oseltamivir phosphate is more common than the United States. These reports discuss neuropsychiatric disturbances after use of oseltamivir phosphate, including delirium, hallucinations, and even fatal injuries.[5] Post-marketing reports prompted Hoffman -LaRoche Inc./Genentech to disclose certain manifestations seen in current studies that could be indicative of neuropsychiatric episodes in the infant population. The studies reported few cases of irritability, lethargy, and staring in the young, non-verbal age group. Although these reports led to warnings on the oseltamivir phosphate package insert, there was no proof that the neuropsychiatric disturbances were caused by oseltamivir phosphate and could be due to influenza-related encephalitis. Further, a fatal toxicity known as “gasping syndrome”can occur from the high exposure to benzyl alcohol in neonates. Oseltamivir phosphate oral suspension contains the metabolite of benzyl alcohol sodium benzoate and should be used with caution in neonates. In post-marketing with oseltamivir phosphate, serious cases of anaphylaxis and serious skin conditions were reported. Oseltamivir phosphate is contraindicated in patients with known hypersensitivity to it or its components.

Patients and families need to be made aware to contact their health care provider immediately upon any signs and symptoms of an allergic-type reaction. Parents should be instructed to call 911/120 for immediate help for any difficulty in breathing, bluish color, changes to lips or skin, and/or signs of severe allergic reaction (swelling to face, mouth, lips).[1]

References

[1] Mortada M, Neuenschwander P, Tekko SS. Influenza and oseltamivir phosphate (Tamiflu) in infants: what you need to know. Pediatr Nurs. 2014;40(1):16-20.

[2] Genentech, Inc. (2012). Tamiflu (oseltamivir phosphate): Highlights of prescribing information. Retrieved from https://www.gene.com/download/pdf/tamiflu_prescribing.pdf

[3] Toovey S, Prinssen EP, Rayner CR, Thakrar BT, Dutkowski R, Koerner A, Chu T, Sirzen-Zelenskaya A, Britschgi M, Bansod S, Donner B: Post-marketing assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: an updated review. Adv Ther. 2012 Oct;29(10):826-48.

[4] Toovey S, Rayner C, Prinssen E, Chu T, Donner B, Thakrar B, Dutkowski R, Hoffmann G, Breidenbach A, Lindemann L, Carey E, Boak L, Gieschke R, Sacks S, Solsky J, Small I, Reddy D: Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review. Drug Saf. 2008;31(12):1097-114.

[5] Mechcatie, E. Abnormal behavior maybe side effect of taking Tamiflu?Neuropsychiatric events lead to warnings. Pediatric News,2006; 40(12), 1.