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 ::  Adverse Effects/...
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DRUG REVIEW
Year : 2009  |  Volume : 55  |  Issue : 3  |  Page : 225-230

Oseltamivir


Department of Pediatrics, Seth GS Medical College and KEM Hospital, Mumbai - 400 012, India

Date of Submission01-Sep-2009
Date of Decision02-Sep-2009
Date of Acceptance11-Sep-2009
Date of Web Publication2-Nov-2009

Correspondence Address:
M S Tullu
Department of Pediatrics, Seth GS Medical College and KEM Hospital, Mumbai - 400 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0022-3859.57411

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 :: Abstract 

Oseltamivir, a selective neuraminidase enzyme inhibitor, has gained worldwide attention in view of Influenza A (H1N1) pandemic. It is one of the most important drugs effective against the novel influenza virus. Oseltamivir is used for the treatment of uncomplicated acute illness due to influenza infection. Early initiation of treatment with the drug provides greater clinical benefits. The drug can also be effectively used for prophylaxis. Oseltamivir is readily absorbed from the gastrointestinal tract and is converted to the active metabolite- oseltamivir carboxylate, which has a wider distribution in the body. Oseltamivir carboxylate is eliminated in the urine with a half-life of 6-10 h. The drug is generally well-tolerated and does not have many clinically significant drug interactions. Nausea and vomiting are the commonest adverse effects associated with its use. The standard adult dose for treatment is 75 mg twice a day for five days and the dose for prophylaxis is 75 mg once daily for at least seven days following contact with an infected individual. The dose needs to be adjusted in patients with renal failure but no adjustments are required in patients with hepatic impairment. Although most of the influenza virus strains are sensitive to oseltamivir, development of drug resistance may limit the clinical utility of the drug in the future.


Keywords: Fever, flu, influenza, neuraminidase, oseltamivir, resistance, virus


How to cite this article:
Tullu M S. Oseltamivir. J Postgrad Med 2009;55:225-30

How to cite this URL:
Tullu M S. Oseltamivir. J Postgrad Med [serial online] 2009 [cited 2019 Aug 19];55:225-30. Available from: http://www.jpgmonline.com/text.asp?2009/55/3/225/57411


Oseltamivir has come into the limelight after the onset of H1N1-Influenza A ('swine flu') pandemic this year. Influenza infections continue to occur worldwide with adverse outcomes in terms of morbidity and mortality in those who are infected. [1] Oseltamivir is a potent selective inhibitor of the neuraminidase enzyme of the influenza viruses, both A and B. [1],[2],[3] Zanamivir, the other drug in this class, is not effective orally and has to be given by dry powder inhalation, thus limiting its use in children. [1],[4]

Oseltamivir is effective against all strains of Influenza A and B (including the avian H5N1, swine origin H1N1 and H9N2 strains). [5],[6],[7] Oseltamivir when administered early, significantly reduces the amount of virus shed, duration of viral shedding and the duration of symptoms. [1],[2],[8],[9],[10] Neuraminidase inhibitors can decrease the duration and severity of influenza-related symptoms if started within 48 h of onset. [1],[3],[8] Their clinical efficacy is around 60-70% and for treatment started within 48 h, the symptoms are reduced by approximately 0.7-1.5 days. [1],[3]


 :: Mechanism of Action Top


The neuraminidase enzyme is responsible for cleaving sialic acid residues on newly formed virions and this is essential for the release of recently formed viral particles from the infected cell. [2],[3],[11],[12] Thus the enzyme helps in the spread of the virus to other cells. [2],[3],[11],[12] The drug blocks the enzyme's ability to cleave sialic acid residues on the surface of the infected cell, thereby inhibiting the release of progeny virions from the infected cells. [1],[13] When exposed to oseltamivir, the influenza virions aggregate on the surface of the host cell, limiting the extent of infection within the mucosal secretions. [3] This helps in reducing the infectivity, as well. [3]


 :: Pharmacology Top


Chemistry

Oseltamivir is the ethyl ester prodrug. It is converted to the active form, oseltamivir carboxylate [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate by ester hydrolysis. [1],[2],[11],[14]

Absorption, distribution and bioavailability

After oral administration, oseltamivir (GS4104) is readily absorbed from the gastrointestinal tract. [13] It is converted to the active metabolite-oseltamivir carboxylate (GS4071) in the liver by hepatic esterases. [2] The active metabolite is distributed throughout the body, including the upper and lower respiratory tract, middle ear, tracheal lining, nasal mucosa and lungs. [1],[2],[11],[12],[13],[15] The absolute bioavailability (of the active metabolite) after oral administration is about 80%. [1],[2],[11],[12],[13],[16]

The active metabolite is detectable in plasma within 30 min with maximum plasma concentrations after 3 to 4 h. [1],[2],[12],[13],[16] After attaining the plasma concentrations, the concentration of the active metabolite declines with a half-life of 6-10 h. [1],[2],[11],[12],[13],[16] The plasma protein binding of oseltamivir carboxylate is only 3%. [2],[11],[13],[15] Co-administration with food has no significant effect on the peak plasma concentration of the drug and can enhance the tolerability in some patients. [1],[2]

Metabolism

Neither oseltamivir nor its active metabolite interacts with cytochrome P450 mixed-function oxidases or glucuronosyltransferases. [1],[2],[11],[16] Hence, the potential for drug- drug interactions is low, and appears to be limited to those arising from competitive inhibition of excretion by the renal tubular epithelial cell anionic transporter. [13],[15]

Metabolism in special populations

As the metabolism of oseltamivir is not compromised in those with liver impairment, dose adjustment is not required in these cases. [2],[17] In the elderly population, exposure to the active metabolite at steady state is about 25% higher compared with young individuals; but this does not necessitate dosage adjustments. [2],[12],[13],[16],[18] As far as children are concerned, young children (1 to 12 years of age) clear the active metabolite oseltamivir carboxylate at a faster rate than older children and adults; infants as young as one-year-old can metabolize and excrete oseltamivir efficiently. [2],[13],[19],[20]

Excretion

The drug and its active metabolite are excreted by glomerular filtration and active tubular secretion. [1],[2],[11],[12],[13],[14],[15] In patients with renal impairment, the metabolite clearance decreases linearly with creatinine clearance, and averages about 23 h after oral administration in individuals with a decreased creatinine clearance (< 30 ml/min). [1],[2],[11],[12],[13],[15],[16] Hence a dosage reduction to 75 mg once daily is recommended for patients with a creatinine clearance < 30 ml/min. [1],[2],[11],[12],[13],[15],[16]


 :: Clinical Uses and Efficacy Top


Oseltamivir is used for the treatment of uncomplicated acute illness due to influenza infection and the outcome is better in patients who have been symptomatic for less than two days. [21] It is also used for prophylaxis of influenza in patients older than one year. [21]

Use for treatment

Oseltamivir (in a dose of 75 mg bid for five days) when administered to healthy adults with naturally acquired febrile influenza infection, reduces the duration of the disease by up to 1.3-1.5 days and the severity of illness by up to 38% (when started within 36 h of the onset of symptoms). [1],[2],[3],[11],[12],[13],[22],[23] The initiation of therapy within the first 12-24 h after the onset of fever significantly reduces the median duration of illness than when therapy is initiated at 48 h. [1],[12],[22],[24] Also, earlier administration of oseltamivir has been shown to reduce the fever duration, symptom severity and the time to return to baseline activity. [1],[13],[24] The effect of oseltamivir is apparent within 24 h of starting the treatment. [9] However, there exists a debate as to whether this efficacy is clinically useful in otherwise healthy patients. [25]

Treatment of influenza illness with oseltamivir reduces lower respiratory tract complications, need for antibacterial agent use and duration of hospitalization in both healthy as well as 'at-risk' adults. [1],[2],[22],[26] The efficacy and safety of oseltamivir in those with chronic respiratory diseases (chronic bronchitis, emphysema, bronchial asthma or bronchiectasis) and cardiac disease has not been as well defined; however, it is effective in this high-risk group, is well tolerated and reduces the incidence of complications and antibiotic use. [2],[11],[13],[27],[28] Rothberg et al. have shown that for unvaccinated or high-risk vaccinated patients, empirical oseltamivir treatment seems to be cost- effective during the influenza season, while for other patients, treatment initiation should be following the results of rapid diagnostic testing. [29]

Use for prophylaxis

Prophylactic use of oseltamivir results in a reduced number of infections and infection-related respiratory illness. [1],[8],[11],[23],[28],[30],[31] Prophylaxis with zanamivir as well as oseltamivir reduces the risk of developing influenza by up to 70-90%. [3],[12],[13],[32] Welliver et al. have shown that prophylactic administration of oseltamivir to household contacts (once daily for seven days within 48 h of the onset of symptoms in the index case), had a protective efficacy against clinical influenza (89%) and also prevented outbreaks within the households. [33] Similar observations have been made by Hayden et al. [34] Also, the use of oseltamivir post- exposure prophylaxis is more cost-effective than amantadine prophylaxis or no prophylaxis. [35] A recent meta-analysis has confirmed the efficacy of extended-duration zanamivir or oseltamivir chemoprophylaxis (> four weeks) for preventing symptomatic influenza among immunocompetent white and Japanese adults. [36]

Use in elderly and high-risk groups

Oseltamivir has been demonstrated to be associated with a 92% reduction in the incidence of laboratory-confirmed clinical influenza in frail old people living in homes for seniors. [37] It also significantly reduced the incidence of secondary complications in these patients. [37] Also, it is effective in reducing Influenza A infection in the elderly and may be effective for household prophylaxis. [38]

As stated earlier, the efficacy of oseltamivir in the treatment of subjects with chronic cardiac and/or respiratory disease is unestablished. [2],[11],[13],[27],[28] Machado et al., have shown that in those who have undergone bone-marrow transplantation, oseltamivir has been shown to be safe and might be an option for treatment during the first six months after transplantation. [39]

Use in children

Studies in children reveal that oral oseltamivir treatment in pediatric patients reduces the median duration of illness by 36 h and decreases the incidence of associated otitis media. [40] Oseltamivir is well-tolerated among asthmatic children and helps reduce symptom duration, improve lung function and reduce asthma exacerbations during influenza infection. [41] Its use has been associated with reduced risks of influenza-related complications and hospitalizations in children and adolescents who are at a high risk of influenza complications. [42] Wallensten et al., evaluated the protective effect, compliance with and side-effects of oseltamivir chemoprophylaxis given to 11-12-year-old school pupils in a secondary school in South West England using a questionnaire and found that the compliance with chemoprophylaxis was high. [43] Oseltamivir is much less effective against Influenza B virus infection in young children, probably because of the low sensitivity of Influenza B viruses to oseltamivir; the effectiveness of oseltamivir against Influenza B being influenced by age and host immunity. [44]


 :: Dosage and Formulations Top


The standard oral doses for treatment and prophylaxis are depicted in [Table 1]. Capsules can be used in adults and older children while oral suspension can be used in children or adults who cannot swallow capsules. Dose adjustment is necessary in those with renal impairment. Patients with a serum creatinine clearance between 10 and 30 ml/min are treated with 75 mg of the drug once daily for five days; the prophylactic dose being 75 mg every other day or 30 mg oral suspension every day.

[Table 2] summarizes the formulations of the drug available. The capsules should be stored at 25°C; variations permitted to 15° to 30°C. It is recommended that the oral suspension be constituted by the pharmacist prior to dispensing to the patient. The constituted suspension should be stored under refrigeration at 2° to 8°C and should not be frozen, and should be used within 10 days of preparation.


 :: Adverse Effects/Side-Effects Top


Oseltamivir is generally well-tolerated with the only clinically important side-effect being mild gastrointestinal upset. [1],[2],[3],[12],[15],[18],[24],[28] The spectrum of adverse effects is given in [Table 3]. The most frequent side-effects include nausea and vomiting (of a mild to moderate degree, usually occurring within the first two days of treatment). [2],[3],[12],[21],[22],[24],[28] The other adverse reactions identified include - diarrhea, abdominal pain, rash, swelling of the face or tongue, toxic epidermal necrolysis, skin/hypersensitivity reactions, hepatitis, abnormal liver function tests, arrhythmias, dizziness, headache, insomnia, vertigo, seizures, confusion, delusions, aggravation of diabetes, fatigue, etc. [2],[11],[12],[13],[21],[28] In many cases, it is not possible to reliably estimate the frequency of these side-effects or establish a causal relationship to oseltamivir exposure. [13],[45] The drug has been linked to psychological disorders and suicides; however, there is currently no evidence of a causal relationship between oseltamivir intake and suicide. [13],[28] Recent data suggests that oseltamivir does not increase the risk of neuropsychiatric events and that influenza itself may cause such events. [28],[45],[46],[47],[48] In a recent study, 51% school children receiving chemoprophylaxis with oseltamivir experienced symptoms such as feeling sick (31.2%), headaches (24.3%) and stomachache (21.1%) amongst other side-effects like feeling tired, vomiting, finding it hard to concentrate, diarrhea and skin rash. [43] Thus, the burden of side-effects needs to be considered when deciding on mass oseltamivir chemoprophylaxis in children [especially given that the symptoms of Influenza A (H1N1) virus influenza are generally mild]. [43] Kitching et al., studied adherence to and side-effects from oseltamivir when offered for prophylaxis (in a cross-sectional anonymised online survey), among pupils from one primary and two secondary schools with confirmed cases of Influenza A(H1N1) virus (London, April-May 2009). [49] Of the 103 respondents (response rate 40%), 95 were estimated to have been offered oseltamivir for prophylaxis, of whom 85 (89%) actually took the drug. [49] Less than half (48%) of primary schoolchildren completed a full course, compared to three-quarters (76%) of secondary schoolchildren. [49] More than half (53%) of all schoolchildren taking prophylactic oseltamivir reported one or more side-effects-gastrointestinal symptoms (feeling sick/nausea, vomiting, diarrhea, stomach pain/cramps) were reported by 40% of children and 18% reported mild neuropsychiatric side-effects (poor concentration/ unable to think clearly, problems sleeping, feeling dazed/confused, bad dreams/nightmares, and behaving strangely). [49] These results confirmed anecdotal evidence of poor adherence and formed part of the body of growing evidence that contributed to policy changes to restrict widespread use of prophylaxis for school contacts of confirmed cases of Influenza A (H1N1) virus. [49] Presently there is no clinical experience with overdose of the drug. [2]


 :: Contraindications Top


Concerned about the uncertainty regarding immature blood- brain barriers, oseltamivir is not recommended for use in children younger than one year. [13] However, the US Food and Drug Administration has recently permitted the use of the drug in infants in emergency situations under emergency use authorization (EUA,treatment dosage for five days-12 mg bid for infants below three months of age, 20 mg bid for infants three to five months of age and 25 mg bid for infants 6-11 months of age). [50] Oseltamivir is contraindicated in those with known hypersensitivity to the drug or to any of the components of the product. [2],[28]


 :: Precautions Top


Oseltamivir is a pregnancy Category C drug and sufficient data is not available to assess the risk to the pregnant woman or developing fetus. [11],[12],[13] Hence, it should be used during pregnancy, only if the potential benefits justify the potential risks to the fetus. [2] However, if treatment or chemoprophylaxis is required for pregnant women during the current pandemic, oseltamivir could be preferred over zanamivir because more information is available on the safety profile of oseltamivir in pregnancy. [2],[51] In lactating rats, oseltamivir is excreted in the milk, but oseltamivir has not been studied in nursing mothers and it is not known, if oseltamivir is secreted in human milk. [2],[11],[13] It should, therefore, be used in lactating mothers, only if the benefit for the mother justifies the potential risk of exposure of the drug to the nursing infant. [2],[11] Both oseltamivir and zanamivir are considered to be compatible with breastfeeding. [2],[51] A mother on either of these drugs can continue to nurse her baby, as the infant is unlikely to have substantial drug exposure. [2],[51]


 :: Special Instructions Top


Early institution of treatment and prophylaxis provide greater benefits. [13] The gastrointestinal disturbance may be reduced by taking oseltamivir after a light snack or with food. [2],[3] Oseltamivir is not a substitute for influenza vaccination and patients should continue receiving vaccination according to the regional/ national guidelines. [11],[13],[52] In animal studies, it has been shown that treatment with oseltamivir does not adversely affect the primary in vivo cellular immune responses or humoral responses to influenza virus infection. Thus, the antibody response to the inactivated vaccine is unlikely to be affected by treatment with the drug. [1],[2],[53]


 :: Drug Interactions Top


Clinically significant drug interactions are unlikely and neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms. [2],[11],[13],[15],[16]


 :: Oseltamivir Resistance Top


Most of the influenza virus strains are sensitive to oseltamivir. However, it has been thought that the development of drug resistance may limit the clinical utility of the drug in the future. [1],[12],[13],[54] The incidence of resistance to the active metabolite is up to 1.5% in Influenza A and has not been reported in Influenza B. [2],[28] Patients with viruses displaying reduced sensitivity clear the virus normally without clinical deterioration. [2] Also, the resistant genotypes are disadvantaged as compared to the wild virus and are likely to be less contagious. [1],[2] Studies have demonstrated a potent anti-viral activity of oseltamivir against all strains of Influenza A and B (including the avian H5N1, swine origin H1N1 and H9N2 strains) in vitro. [5],[6],[7]

de Jong et al., state that in some patients with H5N1 virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication (thus allowing drug resistance to develop). [55] Whether oseltamivir needs to be used in higher doses, or over longer periods of time than currently recommended, is still subject to debate, as also the initiation of treatment late in the course of illness, when there is evidence of ongoing viral replication. [13],[56] There is some evidence that even late treatment initiation can reduce the viral load to undetectable levels which may contribute to survival. [55] In special situations, higher doses of oseltamivir can be safely used in humans and are well tolerated. [57]

Tumpey et al., have demonstrated that recombinant viruses possessing the 1918 NA (or both the 1918 HA and 1918 NA) are effectively inhibited (in tissue culture and mice) by oseltamivir, thus suggesting that the drug can be effective against a re- emergent 1918 or 1918-like virus. [58] It has been suggested that if mutations compromise viral fitness, they might be without clinical significance. However, cases of high- level resistance to oseltamivir in an H5N1 strain raise doubts on this thought. [13],[55],[59]

Mutations associated with amino acid changes in the viral neuraminidase or hemagglutinin or both can cause resistance to oseltamivir. [11],[12],[28],[54] The incidence of development of resistant strains of seasonal H1N1 and H3N2 influenza has been low among adults and adolescents (0.3%); but pediatric studies have demonstrated higher rates. [12],[13],[60] For naturally acquired influenza infections, emergence of variants with decreased neuraminidase susceptibility in cell cultures has been demonstrated to the tune of 1.3% in post-treatment isolates from adults and adolescents and 8.6% in children. [11] Seasonal oseltamivir-resistant Influenza A (H1N1) viruses with NA gene H274Y mutation are transmitted nosocomially and can retain pathogenicity and lethality in high-risk patients. [61]

The NA mutations E119V, R292K, H274Y, and R152K are associated with resistance to oseltamivir in vitro. [7],[11],[12],[13],[28],[54],[62],[63] Cross-resistance between oseltamivir-resistant influenza mutants and zanamivir-resistant influenza mutants has been observed in vitro and two of the three oseltamivir-induced mutations (E119V, H274Y and R292K) in the neuraminidase from clinical isolates occur at the same amino acid residues as two of the three mutations (E119G/A/D, R152K and R292K) observed in zanamivir-resistant virus. [11],[13],[28] It has recently been shown that low levels of oseltamivir carboxylate can be found in the aquatic environment, thus the natural reservoir of influenza virus (dabbling ducks) is exposed to oseltamivir, which could promote the evolution of viral resistance. [64] Early combination chemotherapy and sequential multi-drug chemotherapy have been considered to prevent emergence of drug resistance. [65] Poland et al., state that use of combination antiviral therapy, generation of new guidelines for indications for treatment and point-of-care diagnostic testing, and a universal influenza vaccination recommendation are critical for protecting the population against influenza virus and for preserving the benefits of antiviral agents. [66]

Stephenson et al. have shown that drug resistance emerges at a higher rate in Influenza A subtype H1N1 virus than in Influenza A subtype H3N2 or Influenza B virus after tiered weight-based oseltamivir therapy in children and they state that virological surveillance for patterns of drug resistance is essential for determination of antiviral treatment strategies and for composition of pandemic preparedness stockpiles. [67] Kawai et al., have shown that the clinical effectiveness of oseltamivir for the Influenza A (H1N1) virus was reduced in the 2008-09 season compared with the previous season, especially in children, probably due to the H274Y mutation. [68] In a recent study, it has been reported that pandemic Influenza A (H1N1) viruses currently circulating in New Zealand are sensitive to oseltamivir, but seasonal Influenza A (H1N1) virus (the co-circulating predominant seasonal strain) is resistant to oseltamivir; this co-circulation has the potential for reassortment. [69] It is a bit worrisome that oseltamivir-resistant H1N1 subtype viruses have been recently reported from across the globe including Africa (and the Southern Hemisphere), United States, Europe, Norway, Japan and China. [70],[71],[72],[73],[74],[75],[76],[77] Currently, the drug is clinically effective in the majority of patients. However monitoring for resistance is the need of the hour.

To summarize, oseltamivir is an effective drug for treating uncomplicated acute illness due to influenza infection. Early initiation of treatment with the drug provides greater clinical benefits. The drug is fairly well tolerated and does not have clinically significant drug interactions. Oseltamivir is the mainstay of pharmacological treatment for influenza infections in all age groups.

 
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