Each capsule contains
Oseltamivir phosphate 98.5mg
Equivalent to Oseltamivir…75mg

Oseltamivir is an orally-administered neuraminidase inhibitor reaching all the key sites where the influenza virus multiples, particularly the respiratory tree. The active drug itself, oseltamivir carboxylate, is a specific inhibitor of the NA enzyme of human influenza A and B viruses and avian influenza viruses including the currently circulating A/H5N1 strain.

Oseltamivir is a white crystalline solid with the chemical name (3R, 4R, 5S)-4- acetylamino-5-amino-3 (1-ethylpropoxy)-1-cyclohexena-1-carboxylic acid, ethyl ester phosphate (1:1). The chemical formula is C 16 H 28 N 2 O 4 (free base). The structural formula is follows:

Pharmacodynamic Properties 1

Oseltamivir carboxylate, the active metabolite of os­eltamivir, is a potent and selective inhibitor of neuraminidase. IC 50 values (50% inhibitory concentrations) for oseltamivir carboxylate ranged from 0.0006 to 26.0 μmol/L for laboratory strains of influenza A and B virus and were similar to those reported with zanamivir (a neuraminidase inhibitor which has previously been shown to be a potent inhibitor of influenza A and B strains.

Consistent with in vitro findings, oral oseltamivir demonstrated antiviral ac­tivity against influenza A and influenza B viral strains in animal studies and volunteers with experimentally-induced influenza. The drug re­duced the quantity and duration of viral shedding compared with placebo in volunteers with either strain of the virus.

Viral resistance to oseltamivir carboxylate has emerged in vitro after sequential passages of influenza A (H3N2) virus in cell culture, but the likelihood of in vivo resistance to oseltamivir appears to be low (only a few cases of drug resis­tance have been reported in clinical trials). Finally, the drug appears to have low cytotoxicity relative to its antiviral activity, and does not alter the human immune response to influenza.

Table 1. Overview of the pharmacodynamic properties of oseltamivir and/or its active metabolite oseltamivir carboxylate

• Strong inhibitor of influenza A and B virus replication in vitro (comparable with zanamivir) and in vivo.
• Low cytotoxicity relative to antiviral activity.
• Effective in the prophylaxis and treatment of experimental human influenza A and B virus and naturally acquired infection.
• Low likelihood of resistance to oseltamivir in clinical isolates of influenza A and B.
• No effects on the immune response to infection in humans with experimental or naturally acquired influenza.

Pharmacokinetic Profile 1

Oseltamivir is rapidly absorbed from the gastrointestinal tract after oral admin­istration and is then extensively metabolised, predominantly by hepatic esterases, to its only active metabolite oseltamivir carboxylate. Plasma concentrations of oseltamivir carboxylate have been detected within 30 minutes of an oral oseltamivir dose in volunteers and peaked within 3 to 4 hours at steady state.

Oseltamivir has high (79%) oral bioavailability relative to an intravenous dose of oseltamivir carboxylate and its absorption is not significantly affected by the presence of food.

Oseltamivir carboxylate is rapidly distributed to the primary site of influ­enza virus replication (surface epithelial cells of the respiratory tract) after oral administration of oseltamivir in preclinical studies, and to the middle ear and sinuses in volunteers. Oseltamivir carboxylate is eliminated by primarily by glomerular filtration and renal tubular secretion and has a terminal elimination half-life of 6 to 10 hours.

Clearance of oseltamivir carboxylate is slower in the elderly ≥65 years) and faster in children ( ≤ 12 years) than in adults. In addition, clearance of oseltamivir carboxylate was reduced in patients with severe renal dysfunction.

Clinically significant drug interactions with oseltamivir are unlikely.

Oseltamivir in H5N1 virus infection in humans 2

Controlled clinical trials on the efficacy of neuraminidase inhibitors for treatment and prophylaxis of human avian influenza infections have not been performed. However oseltamivir has been found to be effective in animal models in preventing death and improving survival following infection by A/H5N1 viruses. As in human influenza, the time of commencement of antiviral therapy is directly related to the survival of animals. Highest levels of protection were seen when neuraminidase inhibitors were administered within 48 h of infection. Protective efficacy diminished substantially when neuraminidase inhibitors were administered >60 h after infection. However since the current H5N1 strain of the influenza virus has a longer incubation period (2-8 days), oseltamivir should be started whenever the patient presents with symptoms. Reports of humans infected with H5N1 from Thailand suggest that patients who had survived after oseltamivir treatment appeared to have received the agent earlier than those who subsequently died (4.5 days vs 9 days after disease onset).

Furthermore, the higher virulence of recent isolates of A/H5N1 viruses appears to reduce the efficacy of neuraminidase inhibitors in animal models. A higher daily dose (10 mg/kg/d vs 1 mg/kg/d in mice) and a longer duration of treatment (8 days vs 5 days) of oseltamivir significantly improves survival of animals. The findings suggest that H5N1 infection in humans may require higher doses and for a prolonged duration (7-10 days) than those currently recommended for seasonal influenza. Increased dose is especially indicated in patients with a high viral load due to delayed presentation, severe diseases with shock, or poor oral drug absorption as a result of severe diarrhea. Although oseltamivir has been administered in high doses to healthy volunteers at more than the therapeutic doses without significant adverse reactions, any potential toxicity associated with high-dose regimens must be closely monitored.

Oseltamivir in Seasonal Influenza
Trials of Oseltamivir for both treatment and prevention of influenza virus infection have been conducted during periods of seasonal influenza activity. Studies have confirmed oseltamivir to be an effective antiviral agent when administered orally for the prevention and treatment of experimental influenza A infections. 3

Treatment of Healthy Adults
Two large studies have evaluated the efficacy of oseltamivir treatment in over 1300 healthy, non-immunised adults 18 to 65 years of age who presented with a febrile respiratory illness of no more than 36 hours, along with one respiratory symptom (cough, sore throat, or nasal) and one constitutional symptom (headache, malaise, myalgia, sweats or chills, or fatigue).

In the study by, Treanov et al, 4 influenza was confirmed in 374 of the subjects, and oseltamivir treatment reduced the median duration of illness by more than 30% and the severity of illness by 38%.

In the other study by Nicholson et al, 5 duration of illness was significantly shorter by 25%. Both the studies demonstrated a reduction in fever and a resolution of symptoms as soon as 24 hours after initiation of treatment. Furthermore, treated patients had a lower frequency of secondary complications than did the untreated patients secondary (complications such as bronchitis and sinusitis occurred in 15% of placebo recipients compared with 7% of oseltamivir recipients.

Early initiation of treatment appears to be the most important determinant of treatment efficacy, as demonstrated in the 2003 Immediate Possibility to Access Treatment (IMPACT) study, 6 which directly investigated the relationship between the time to the initiation of oseltamivir therapy and the duration of illness and other efficacy measures in 1426 patients ranging in age from 12 to 70 years. Initiation of therapy within the first 12 hours after the onset of fever reduced the total median illness duration by 74.6 hour (3.1 days; 41%) more than the intervention at 48 hours. In addition, the earlier administration of oseltamivir further reduced the duration of fever, severity of symptoms and the time to return to baseline activity and health scores. The IMPACT study demonstrates the value of early presentation and diagnosis of patients with influenza and their treatment with oseltamivir.

 Impact of Treatment on Complications
Treatment of influenza with oseltamivir plays an important role in preventing lower respiratory tract infections (LRTIs) including acute bronchitis, pneumonia and exacerbations of underlying airway diseases. 7,8

Prospectively collected data on LRTIs and antibiotic use from 3564 subjects with influenza-like illness enrolled in 10 placebo-controlled, double-blind trials of oseltamivir treatment demonstrated a 50% reduction in hospitalization rates, 26.7% reduction in the incidence of influenza-related lower respiratory tract infections resulting in reduction in antibiotic therapy by 55%. In another retrospective cohort study a 28% reduction in the risk of pneumonia, 11% reduction in antibiotic dispensing and 26% reduction in hospitalisations was seen for patients with influenza-like illness receiving oseltamivir compared to those not receiving oseltamivir.

Co-infection with Streptococcus pneumoniae and influenza can have a syngergistic effect on disease severity, leading to excess mortality. In a mouse model it was demonstrated that the shipping of sialic acid from the lung by influenza virus neuraminidase potentiated development of pneumonia by exposing receptors for pneumococcal adherence. Oseltamivir improved survival of mice, independent of viral replication and morbidity from influenza. Thus, treatment of influenza with NIs may play an important role in preventing exacerbation of pneumonia. 9

Prophylaxis in healthy adults
Several large, controlled studies of prophylaxis have demonstrated that oseltamivir is effective in preventing clinical influenza in healthy adults when it is used either as prophylaxis after exposure for close contacts, such as household members, or as seasonal prophylaxis in the community.

In one of the studies 1559 healthy, non-immunized adults 18 to 65 years old were randomly assigned to receive either oseltamivir (75 mg od or bd) or placebo for 6 weeks during a peak period of local influenza virus activity. Subjects were monitored for febrile (temperature ≥ 990 F), respiratory and systemic symptoms of influenza. The overall protective efficacy of oseltamivir against naturally occurring influenza illness was 74%. Oseltamivir reduced both incidence of illness (1.2 or 1.3% with od or bd v/s 4.8% with placebo) & laboratory evidence of infection by 5.3% compared to 10.6% for placebo. 10

Households are an important site of influenza virus transmission during community outbreaks. It was found that post-exposure prophylaxis (PEP) with oseltamivir was 58.5% more effective in reducing secondary cases of influenza illness in households (and 68% more effective in individuals), compared with treating index cases alone. 11

In another study by Welliver et al, efficacy of oseltamivir in preventing clinical influenza was 89% prevention of initial viral infection was 63%. The study demonstrates that 75 mg of oseltamivir once daily for 7 days was highly effective in protecting close contacts against influenza illness when initiated within 48 hours of exposure to a symptomatic case of influenza. Oseltamivir also effectively prevented further transmission of influenza within households following prompt initiation of short-term prophylaxis in families. 12

Prophylaxis in High-Risk Elderly or chronically Ill Populations
There is some data on the use of these drugs to prevent disease in the most vulnerable patients, including the elderly. One important double-blind, placebo-controlled, randomized study demonstrated that the use of oseltamivir for seasonal prophylaxis in residential homes for elderly persons led to a 92% reduction in the incidence of laboratory confirmed influenza, even though the great majority of the elderly residents had received the appropriate vaccine for the season. Thus, antiviral prophylaxis provided important additional protection to that conferred by vaccination. Therefore, efforts to improve early recognition of influenza symptoms in the elderly and rapid response by staff members will enhance the effectiveness of oseltamivir prophylaxis for control of outbreaks in institutions. 13

Treatment in Children
The benefits of oseltamivir treatment have also been demonstrated in children aged ≥ 1 year.49 Oseltamivir treatment resolved illness 36 h earlier than in the placebo arm. In young children, the main secondary complication arising from influenza infection is otitis media. This study demonstrated the ability of oseltamivir treatment to reduce the incidence of new diagnoses of otitis by 44%, a clear demonstration of the benefits of a systemic therapy. In children with mild to moderate asthma, there was a small but significant improvement in the forced expiratory volume in 1 s (FEV1). 14

Antiflu may be taken with or without food. However, when taken with food, tolerability may be enhanced in some patients.

Standard Dosage - Treatment of Influenza:

Adults and Adolescents : The recommended oral dose of Antiflu for treatment of influenza in adults and adolescents 13 years and older is 75 mg twice daily for 5 days. Treatment should begin within 2 days of onset of symptoms of influenza.

Standard Dosage - Prophylaxis of Influenza:

Adults & Adolescents : The recommended oral dose of Antiflu for prophylaxis of influenza in adults and adolescents 13 years and older following close contact with an infected individual is 75 mg once daily for at least 10 days. Therapy should begin within 2 days of exposure. The recommended dose for prophylaxis during a community outbreak of influenza is 75 mg once daily. Safety and efficacy have been demonstrated for up to 6 weeks. The duration of protection lasts for as long as dosing is continued.

Special Dosage Instructions

Hepatic Impairment : The safety and pharmacokinetics in patients with hepatic impairment have not been evaluated.

Renal Impairment : For plasma concentrations of oseltamivir carboxylate predicted to occur following various dosing schedules in patients with renal impairment.

Treatment of Influenza

Dose adjustment is recommended for patients with creatinine clearance between 10 and 30 mL/min receiving oseltamivir for the treatment of influenza. In these patients it is recommended that the dose be reduced to 75 mg of oseltamivir once daily for 5 days. No recommended dosing regimens are available for patients undergoing routine hemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease.

Prophylaxis of Influenza

For the prophylaxis of influenza, dose adjustment is recommended for patients with creatinine clearance between 10 and 30 mL/min receiving oseltamivir. In these patients it is recommended that the dose be reduced to 75 mg of Antiflu every other day. No recommended dosing regimens are available for patients undergoing routine hemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease.

Geriatric Patient : No dose adjustment is required for geriatric patients

Dosage in H5N1 virus infection (avian influenza) in humans

Due to the high pathogenic nature of the H5N1 viral strain, WHO recommends that in patients who do not respond to standard doses, clinicians should consider increasing the dose and duration of treatment (7-10 days) with oseltamivir keeping in mind that 300 mg/day is associated with increased side effects. Administration of drug should also be considered in patients presenting later in the course of the disease.

Oseltamivir was first launched in 1999 and approximately 20 million patients have been exposed to the drug since the introduction into the market. No important safety concerns have evolved which might limit the suitability of oseltamivir for the treatment and prevention of influenza in all approved patient populations.

The most frequently reported events were consistent with the events observed during clinical trials: nausea, vomiting, diarrhoea and dizziness. In addition, hypersensitivity reactions mainly allergic skin reactions such as rash, dermatitis, urticaria, eczema, face oedema and erythema were reported rarely. In very rare cases, more severe reactions such as Stevens- Johnson-Syndrome and erythema multiforme were reported. Very rare cases of hepatitis and elevated liver enzymes have been reported in patients with influenza-like illness receiving oseltamivir.

Overdose
As yet, there is no experience with overdose, although the anticipated manifestations of acute overdose would be nausea, with or without accompanying emesis. Single doses of up to 1000 mg of oseltamivir have been well tolerated apart from nausea and/or vomiting.

General

• There is no evidence for efficacy of oseltamivir in any illness caused by agents other than influenza viruses
  Types A and B.
• Use of oseltamivir should not affect the evaluation of individuals for annual influenza vaccination
• Efficacy of oseltamivir in patients who begin treatment after 40 hours of symptoms has not been established.
• Efficacy of oseltamivir in the treatment of subjects with chronic cardiac disease and/or respiratory disease has not been established. No difference in the incidence of complications was observed between the treatment and placebo groups in this population. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization.
• Safety and efficacy of repeated treatment or prophylaxis courses have not been studied.
• Efficacy of oseltamivir for treatment or prophylaxis has not been established in immunocompromised patients.

Drug Interactions

Information derived from pharmacology and pharmacokinetic studies of oseltamivir suggests that clinically significant drug interactions are unlikely.

Oseltamivir is extensively converted to oseltamivir carboxylate by esterases, located predominantly in the liver. Drug interactions involving competition for esterases have not been extensively reported in literature. Low protein binding of oseltamivir and oseltamivir carboxylate suggests that the probability of drug displacement interactions is low.

In vitro studies demonstrate that neither oseltamivir nor oseltamivir carboxylate is a good substrate for P450 mixed-function oxidases or for glucuronyl transferases.

Coadministration of probenecid results in an approximate twofold increase in exposure to oseltamivir carboxylate due to a decrease in active anionic tubular secretion in the kidney. However, due to the safety margin of oseltamivir carboxylate, no dose adjustments are required when coadministering with probenecid.

Hepatic Impairment

The safety and pharmacokinetics in patients with hepatic impairment have not been evaluated.

Renal Impairment

Dose adjustment is recommended for patients with a serum creatinine clearance <30 mL/min (see dosage and administration )

Pregnancy

Pregnancy Category C : There are insufficient human data upon which to base an evaluation of risk of oseltamivir to the pregnant woman or developing fetus. Because animal reproductive studies may not be predictive of human response and there are no adequate and well-controlled studies in pregnant women, oseltamivir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

In lactating rats, oseltamivir and oseltamivir carboxylate are excreted in the milk. It is not known whether oseltamivir or oseltamivir carboxylate is excreted in human milk. oseltamivir should, therefore, be used only if the potential benefit for the lactating mother justifies the potential risk to the breast-fed infant

Geriatric Use

No dose adjustment is required for geriatric patients

Pediatric Use

The safety and efficacy of oseltamivir in pediatric patients younger than 1 year of age have not been studied. Oseltamivir is not indicated for either treatment or prophylaxis of influenza in pediatric patients younger than 1 year of age because of uncertainties regarding the rate of development of the human blood-brain barrier and the unknown clinical significance of non-clinical animal toxicology data for human infants

Influenza is more readily transmissible than the severe acute respiratory syndrome (SARS) coronavirus. Not surprisingly then, in the 21st century, that complete global spread of a new pandemic virus is predicted to occur very soon. In these circumstances vaccines are likely to be in short supply, if indeed any is available. It is fortunate then that we have a new weapon in hand for the next pandemic. The neuraminidase inhibitors, a new class of drugs active against all influenza subtypes, have proven efficacy in the treatment and prevention of influenza. Two drugs are licensed worldwide, oseltamivir (Antiflu) and zanamivir (administered by inhalation). Oseltamivir has been shown to be efficacious and well tolerated in all populations studied and has been approved for use in most regions of the world.

The recommended dose of Antiflu for the treatment of influenza, in adults and adolescents 13 years of age and older, is 150 mg per day, given as 75 mg twice a day for five days. The recommended oral dose of Antiflu for prophylaxis of influenza in adults and adolescents 13 years and older following close contact with an infected individual is 75 mg once daily for at least 10 days . Safety and efficacy have been demonstrated for up to 6 weeks.

There are no clinical data available for the use of oseltamivir in a pandemic. As the duration of viral replication may be prolonged in cases of H5N1 infection, clinicians should consider increasing the duration of treatment to seven to ten days in patients who are not showing a clinical response. In cases of severe infection with the H5N1 virus, clinicians may need to consider increasing the recommended daily dose or the duration of treatment, keeping in mind that doses above 300 mg per day are associated with increased side effects. For all treated patients, consideration should be given to taking serial clinical samples for later assay to monitor changes in viral load, to assess drug susceptibility, and to assess drug levels. These samples should be taken only in the presence of appropriate measures for infection control. 15

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