Source: Health Sciences Authority (SG) Publisher: Manufactured by: Natco Pharma Limited, Kothur – 509 228, Rangareddy District, Telangana, India Marketed by: Natco Pharma Asia Pte Ltd., 111, North Bridge Road, # 23-05 Peninsula Plaza, Singapore 179098 ...
Pharmacotherapeutic group: Antiviral
ATC code: J05AH02
Oseltamivir phosphate is a pro-drug of the active metabolite (oseltamivir carboxylate). The active metabolite is a selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteins found on the virion surface. Viral neuraminidase enzyme activity is primarily important for the release of recently formed virus particles from infected cells, and for the further spread of infectious virus in the body. It has also been suggested that neuraminidase can play a role in viral entry into uninfected cells.
Oseltamivir carboxylate inhibits influenza A and B neuraminidases in vitro. Oseltamivir phosphate inhibits influenza virus infection and replication in vitro. Oseltamivir given orally inhibits influenza A and B virus replication and pathogenicity in vivo in animal models of influenza infection at antiviral exposures similar to that achieved in man with 75 mg twice daily.
Antiviral activity of oseltamivir was supported for influenza A and B by experimental challenge studies in healthy volunteers.
Neuraminidase enzyme IC50 values for oseltamivir for clinically isolated influenza A ranged from 0.1 nM to 1.3 nM, and for influenza B was 2.6 nM. Higher IC50 values for influenza B, up to a median of 8.5 nM, have been observed in published trials.
Clinical studies: The risk of emergence of influenza viruses with reduced susceptibility or frank resistance to oseltamivir has been examined during clinical studies. Patients who were found to carry oseltamivir-resistant virus generally did so transiently and showed no worsening of the underlying symptoms. In some pediatric patients, oseltamivir-resistant virus was detected for a prolonged period compared to patients carrying oseltamivir-sensitive virus; however these patients showed no prolongation of influenza symptoms.
Incidence of Oseltamivir Resistance in Clinical Studies:
| Patient Population | Patients with Resistance Mutations (%) | |
|---|---|---|
| Phenotyping* | Geno- and Phenotyping* | |
| Adults and adolescents | 4/1245 (0.32%) | 5/1245 (0.4%) |
| Children (1-12 years) | 19/464 (4.1%) | 25/464 (5.4%) |
* Full genotyping was not performed in all studies.
There has been no evidence for emergence of drug resistance associated with the use of oseltamivir phosphate capsules in clinical studies conducted to date in post-exposure (7 days), post-exposure within household groups (10 days) and seasonal (42 days) prevention of influenza.
The rate of emergence of resistance may be higher in the youngest age groups, and in immunosupressed patients. Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivir-resistant laboratory strains of influenza viruses have been found to contain mutations in N1 and N2 neuraminidases. Resistance mutations tend to be viral subtype specific (including those found in H5N1 variants).
Clinical and surveillance data: Naturally occurring mutations in influenza A/H1N1 virus associated with reduced susceptibility to oseltamivir in vitro have been detected in patients who, based on the reported information, have not been exposed to oseltamivir.
Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivirresistant laboratory strains of influenza viruses have been found to contain mutations in N1and N2 neuraminidases. Resistance mutations tend to be viral sub-type specific. Since 2007 resistance associated H275Y mutation in seasonal H1N1 strains has become widespread. The susceptibility to oseltamivir and the prevalence of such viruses appear to vary seasonally and geographically. In 2008, H275Y was found in >99% of circulating H1N1 influenza isolates in Europe. The 2009 H1N1 influenza (“swine flu”) was almost uniformly susceptible to oseltamivir, with only sporadic reports of resistance in connection with both therapeutic and prophylactic regimens.
Oseltamivir is effective only against illnesses caused by influenza virus. Statistical analyses are therefore presented only for influenza-infected subjects. In the pooled treatment study population, which included both influenza-positive and -negative subjects (ITT), primary efficacy was reduced proportional to the number of influenza-negative individuals. In the overall treatment population, influenza infection was confirmed in 67% (range 46% to 74%) of the recruited patients. Of the elderly subjects, 64% were influenza-positive and of those with chronic cardiac and/or respiratory disease 62% were influenza-positive. In all phase III treatment studies, patients were recruited only during the period in which influenza was circulating in the local community.
Adults and adolescents 13 years of age and older: Patients were eligible if they reported within 36 hours of onset of symptoms, had fever ≥37.8°C, accompanied by at least one respiratory symptom (cough, nasal symptoms or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue or headache). In a pooled analysis of all influenza-positive adults and adolescents (N=2413) enrolled into treatment studies, oseltamivir 75 mg twice daily for 5 days reduced the median duration of influenza illness by approximately one day from 5.2 days (95% CI 4.9 – 5.5 days) in the placebo group to 4.2 days (95% CI 4.0 – 4.4 days; p ≤ 0.0001).
The proportion of subjects who developed specified lower respiratory tract complications (mainly bronchitis) treated with antibiotics was reduced from 12.7% (135/1063) in the placebo group to 8.6% (116/1350) in the oseltamivir treated population (p = 0.0012).
Treatment of influenza in high risk populations: The median duration of influenza illness in elderly subjects (≥65 years) and in subjects with chronic cardiac and/or respiratory disease receiving oseltamivir 75 mg twice daily for 5 days was not reduced significantly. The total duration of fever was reduced by one day in the groups treated with oseltamivir. In the influenza-positive elderly, oseltamivir significantly reduced the incidence of specified lower respiratory tract complications (mainly bronchitis) treated with antibiotics from 19% (52/268) in the placebo group to 12% (29/250) in the oseltamivir treated population (p = 0.0156).
In influenza-positive patients with chronic cardiac and/or respiratory disease, the combined incidence of lower respiratory tract complications (mainly bronchitis) treated with antibiotics was 17% (22/133) in the placebo group and 14% (16/118) in the oseltamivir treated population (p = 0.5976).
Treatment of influenza in children: In a study of otherwise healthy children (65% influenzapositive) aged 1 to 12 years (mean age 5.3 years) who had fever (≥37.8°C) plus either cough or coryza, 67% of influenza-positive patients were infected with influenza A and 33% with influenza B. Oseltamivir treatment, started within 48 hours of onset of symptoms, significantly reduced the time to freedom from illness (defined as the simultaneous return to normal health and activity and alleviation of fever, cough and coryza) by 1.5 days (95% CI 0.6 – 2.2 days; p < 0.0001) compared to placebo. Oseltamivir reduced the incidence of acute otitis media from 26.5% (53/200) in the placebo group to 16% (29/183) in the oseltamivir treated children (p = 0.013).
A second study was completed in 334 asthmatic children aged 6 to 12 years old of which 53.6% were influenza-positive. In the oseltamivir treated group, the median duration of illness was not reduced significantly. By day 6 (the last day of treatment) FEV1 had increased by 10.8% in the oseltamivir treated group compared to 4.7% on placebo (p = 0.0148) in this population.
Treatment of influenza B infection: Overall, 15% of the influenza-positive population were infected by influenza B, proportions ranging from 1 to 33% in individual studies. The median duration of illness in influenza B infected subjects did not differ significantly between the treatment groups in individual studies. Data from 504 influenza B infected subjects were pooled across all studies for analysis. Oseltamivir reduced the time to alleviation of all symptoms by 0.7 days (95% CI 0.1 – 1.6 days; p = 0.022) and the duration of fever (≥37.8°C), cough and coryza by one day (95% CI 0.4 – 1.7 days; p < 0.001) compared to placebo.
The efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstrated in a post-exposure prevention study in households and two seasonal prevention studies. The primary efficacy parameter for all of these studies was the incidence of laboratoryconfirmed influenza. The virulence of influenza epidemics is not predictable and varies within a region and from season to season, therefore the number needed to treat (NNT) in order to prevent one case of influenza illness varies.
Post-exposure prevention: In a study in contacts (12.6% vaccinated against influenza) of an index case of influenza, oseltamivir 75 mg once daily was started within 2 days of onset of symptoms in the index case and continued for seven days. Influenza was confirmed in 163 out of 377 index cases. Oseltamivir significantly reduced the incidence of clinical influenza illness occurring in the contacts of confirmed influenza cases from 24/200 (12%) in the placebo group to 2/205 (1%) in the oseltamivir group (92% reduction [95% CI 6 – 16; p ≤ 0.0001]). The number needed to treat (NNT) in contacts of true influenza cases was 10 (95% CI 9–12) and was 16 (95% CI 15 – 19) in the whole population (ITT) regardless of infection status in the index case.
The efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstrated in a post-exposure prevention study in households that included adults, adolescents, and children aged 1 to 12 years, both as index cases and as family contacts. The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza in the households. Oseltamivir prophylaxis lasted for 10 days. In the total population, there was a reduction in the incidence of laboratory-confirmed clinical influenza in households from 20% (27/136) in the group not receiving prevention to 7% (10/135) in the group receiving prevention (62.7% reduction [95% CI 26.0 – 81.2; p = 0.0042]). In households of influenza-infected index cases, there was a reduction in the incidence of influenza from 26% (23/89) in the group not receiving prevention to 11% (9/84) in the group receiving prevention (58.5% reduction [95% CI 15.6 – 79.6; p = 0.0114]).
According to subgroup analysis in children at 1 to 12 years of age, the incidence of laboratoryconfirmed clinical influenza among children was significantly reduced from 19% (21/111) in the group not receiving prevention to 7% (7/104) in the group receiving prevention (64.4% reduction [95% CI 15.8 – 85.0; p = 0.0188]). Among children who were not already shedding virus at baseline, the incidence of laboratory-confirmed clinical influenza was reduced from 21% (15/70) in the group not receiving prevention to 4% (2/47) in the group receiving prevention (80.1% reduction [95% CI 22.0 – 94.9; p = 0.0206]). The NNT for the total paediatric population was 9 (95% CI 7 – 24) and 8 (95% CI 6, upper limit not estimable) in the whole population (ITT) and in paediatric contacts of infected index cases (ITTII), respectively.
Prevention during an influenza epidemic in the community: In a pooled analysis of two other studies conducted in unvaccinated otherwise healthy adults, oseltamivir 75 mg once daily given for 6 weeks significantly reduced the incidence of clinical influenza illness from 25/519 (4.8%) in the placebo group to 6/520 (1.2%) in the oseltamivir group (76% reduction [95% CI 1.6 – 5.7; p = 0.0006]) during a community outbreak of influenza. The NNT in this study was 28 (95% CI 24 – 50).
A study in elderly residents of nursing homes, where 80% of participants received vaccine in the season of the study, oseltamivir 75 mg once daily given for 6 weeks significantly reduced the incidence of clinical influenza illness from 12/272 (4.4%) in the placebo group to 1/276 (0.4%) in the oseltamivir group (92% reduction [95% CI 1.5 – 6.6; p = 0.0015]). The NNT in this study was 25 (95% CI 23 – 62).
Specific studies have not been conducted to assess of the reduction in the risk of complications.
Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate (pro-drug) 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.
The mean volume of distribution at steady state of the oseltamivir carboxylate is approximately 23 litres in humans, a volume equivalent to extracellular body fluid. Since neuraminidase activity is extracellular, oseltamivir carboxylate distributes to all sites of influenza virus spread. The binding of the oseltamivir carboxylate to human plasma protein is negligible (approximately 3%).
Oseltamivir is extensively converted to oseltamivir carboxylate by esterases located predominantly in the liver. In vitro studies demonstrated that neither oseltamivir nor the active metabolite is a substrate for, or an inhibitor of, the major cytochrome P450 isoforms. No phase 2 conjugates of either compound have been identified in vivo.
Absorbed oseltamivir is primarily (>90%) eliminated by conversion to oseltamivir carboxylate. It is not further metabolised and is eliminated in the urine. Peak plasma concentrations of oseltamivir carboxylate decline with a half-life of 6 to 10 hours in most subjects. The active metabolite is eliminated entirely by renal excretion. Renal clearance (18.8 l/h) exceeds glomerular filtration rate (7.5 l/h) indicating that tubular secretion occurs in addition to glomerular filtration. Less than 20% of an oral radiolabelled dose is eliminated in faeces.
Administration of 100 mg oseltamivir phosphate twice daily for 5 days to patients with various degrees of renal impairment showed that exposure to oseltamivir carboxylate is inversely proportional to declining renal function. For dosing, see section 3.2.
In vitro studies have concluded that exposure to oseltamivir is not expected to be increased significantly nor is exposure to the active metabolite expected to be significantly decreased in patients with hepatic impairment (see section 3.2).
The pharmacokinetics of oseltamivir have been evaluated in single-dose pharmacokinetic studies in children aged 1 to 16 years. Multiple-dose pharmacokinetics were studied in a small number of children enrolled in a clinical efficacy study. Younger children cleared both the prodrug and its active metabolite faster than adults, resulting in a lower exposure for a given mg/kg dose. Doses of 2 mg/kg give oseltamivir carboxylate exposures comparable to those achieved in adults receiving a single 75 mg dose (approximately 1 mg/kg). The pharmacokinetics of oseltamivir in children over 12 years of age are similar to those in adults.
Exposure to the active metabolite at steady state was 25 to 35% higher in elderly (age 65 to 78 years) compared to adults less than 65 years of age given comparable doses of oseltamivir. Half-lives observed in the elderly were similar to those seen in young adults. On the basis of drug exposure and tolerability, dosage adjustments are not required for elderly patients unless there is evidence of severe renal impairment (creatinine clearance below 30 ml/min) (see section 3.2).
A pooled population pharmacokinetic analysis indicates that the oseltamivir phosphate capsules dosage regimen described in Section 3.2 Posology and Method of Administration results in lower exposure (30% on average across all trimesters) to the active metabolite in pregnant women compared to non-pregnant women. The lower predicted exposure however, remains above inhibitory concentrations (IC95 values) and at a therapeutic level for a range of influenza virus strains. In addition, there is evidence from observational studies showing benefit of the current dosing regimen in this patient population. Therefore, dose adjustments are not recommended for pregnant women in the treatment or prophylaxis of influenza.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity and genotoxicity. Results of the conventional rodent carcinogenicity studies showed a trend towards a dose-dependent increase in the incidence of some tumours that are typical for the rodent strains used. Considering the margins of exposure in relation to the expected exposure in the human use, these findings do not change the benefitrisk of oseltamivir phosphate capsules in its adopted therapeutic indications.
Teratology studies have been conducted in rats and rabbits at doses of up to 1500 mg/kg/day and 500 mg/kg/day, respectively. No effects on foetal development were observed. A rat fertility study up to a dose of 1500 mg/kg/day demonstrated no adverse effects on either sex. In pre- and post-natal rat studies, prolonged parturition was noted at 1500 mg/kg/day: the safety margin between human exposure and the highest no-effect dose (500 mg/kg/day) in rats is 480-fold for oseltamivir and 44-fold for the active metabolite, respectively. Foetal exposure in the rats and rabbits was approximately 15 to 20% of that of the mother.
In lactating rats, oseltamivir and the active metabolite are excreted in milk. Limited data indicate that oseltamivir and the active metabolite are excreted in human milk. Extrapolation of the animal data provides estimates of 0.01 mg/day and 0.3 mg/day for the respective compounds.
A potential for skin sensitisation to oseltamivir was observed in a “maximisation” test in guinea pigs. Approximately 50% of the animals treated with the unformulated active ingredient showed erythema after challenging the induced animals. Reversible irritancy of rabbits' eyes was detected.
Whereas very high oral single doses of oseltamivir phosphate had no effect in adult rats, such doses resulted in toxicity in juvenile 7-day-old rat pups, including death. These effects were seen at doses of 657 mg/kg and higher. At 500 mg/kg, no adverse effects were seen, including upon chronic treatment (500 mg/kg/day administered from 7 to 21 days post partum).
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