Mechanism of action
Antiviral drug. Oseltamivir is its prodrug, its active metabolite (oseltamivir carboxylate, OK) is an effective and selective neuraminidase inhibitor of influenza virus type A and B, an enzyme that catalyzes the release of newly formed viral particles from infected cells, their penetration into uninfected respiratory epithelial cells, and further the spread of the virus in the body. Stops the growth of the influenza virus in vitro and suppresses the replication of the virus and its pathogenicity in vivo, reduces the allocation of influenza A and B viruses from the body. The OC concentration necessary for inhibiting neuraminidase by 50% (IC.50), is 0.1-1.3 nM for the influenza A virus and 2.6 nM for the influenza B virus. Median values IC50 for influenza B virus is slightly higher and is 8.5 nM.
Clinical efficacy
In the studies, Tamiflu had no effect on the formation of anti-influenza antibodies, including the production of antibodies in response to the introduction of an inactivated influenza vaccine.
Studies of natural influenza infection
In clinical studies conducted during seasonal influenza infection, patients began to receive Tamiflu no later than 40 hours after the onset of the first symptoms of influenza infection. 97% of patients were infected with influenza A virus and 3% of patients with influenza B. B. Tamiflu significantly reduced the period of clinical manifestations of influenza infection (by 32 hours). In patients with confirmed influenza diagnosis who took Tamiflu, the severity of the disease, expressed as the area under the curve for the total symptom index, was 38% less than in patients who were half-
who took placebo. Moreover, in young patients without concomitant diseases, Ta-
miflu reduced about 50% of the frequency of complications of influenza, requiring the use of antibiotics (bronchitis, pneumonia, sinusitis, otitis media). Clear evidence was obtained of the effectiveness of the drug with respect to secondary efficacy criteria related to antiviral activity: Tamiflu® caused both a shortening of the time of virus isolation from the body and a decrease in the area under the "viral titers-time" curve.
Data obtained in a study on the therapy of Tamiflu in elderly and senile patients,show that taking Tamiflu 75 mg twice daily for 5 days was accompanied by a clinically significant decrease in the median period of clinical manifestations of influenza infection, similar to that in older adults, but the differences did not reach statistical significance. In another study, patients with influenza older than 13 years who had concomitant chronic cardiovascular and / or respiratory diseases received Tamiflu® in the same dosing regimen or placebo. Differences in the median of the period before the decrease in clinical manifestations of influenza infection in the Tamiflu and placebo groups were not, however, the period of temperature increase with the use of Tamiflu ® was reduced by approximately 1 day. The proportion of patients who isolated the virus on days 2 and 4 became significantly less. The safety profile of Tamiflu in patients at risk did not differ from that in the general population of adult patients.
Treatment of influenza in children
In children aged 1-12 years (mean age 5.3 years) who had fever (> 37.8 ° C) and one of the symptoms on the part of the respiratory system (cough or rhinitis) during the circulation of the influenza virus among the population, a double-blind, placebo- controlled trial. 67% of patients were infected with influenza A and
33% of patients were influenza B. The drug Tamiflu (when taken no later than 48 hours after the onset of the first symptoms of influenza infection) significantly reduced the duration of the disease (by 35.8 hours) compared with placebo. The duration of the disease was defined as the time to stopping coughing, nasal congestion, the disappearance of fever, a return to normal activity. In the group of children receiving Tamiflu, the incidence of acute otitis media decreased by 40% compared with the placebo group. Recovery and return to normal activity occurred almost 2 days earlier in children receiving Tamiflu, compared with the placebo group.
In another study, children aged 6-12 years with bronchial asthma participated; 53.6% of patients had an influenza infection confirmed serologically and / or in culture. The median duration of the disease in the group of patients receiving Tamiflu did not significantly decrease. But by the last 6th day of Tamiflu therapy, the volume of forced expiration in 1 sec (FEV1) increased by 10.8% compared with 4.7% in patients receiving placebo (p = 0.0148).
Prevention of influenza in adults and adolescents
The prophylactic efficacy of Tamiflu in the case of natural influenza A and B infection was demonstrated in 3 separate clinical trials of Phase III. On the background of taking Tamiflu, influenza caused about 1% of patients. Tamiflu also significantly reduced the frequency of virus isolation and prevented transmission of the virus from one member of the family to another.
Adults and adolescents who were in contact with a sick family member began receiving Tamiflu within two days of the onset of flu symptoms among family members and continued it for 7 days, which reliably reduced the incidence of influenza in 92% of the contactees.
In unvaccinated and generally healthy adults aged 18-65 years, taking Tamiflu during the flu epidemic significantly reduced the incidence of influenza (by 76%). Patients took the drug for 42 days.
In elderly and elderly people who were in nursing homes, 80% of whom were vaccinated before the season when the study was conducted, Tamiflu ® was fairly reducing the incidence of influenza by 92%. In the same study, Tamiflu reliably (by 86%) reduced the incidence of complications of influenza: bronchitis, pneumonia, sinusitis.Patients took the drug for 42 days.
Prevention of influenza in children
The prophylactic efficacy of Tamiflu with natural influenza infection was demonstrated in children from 1 year to 12 years after contact with an affected family member or someone from a constant environment. The main parameter of effectiveness was the frequency of a laboratory-confirmed influenza infection. In children receiving Tamiflu® / powder to prepare a suspension for oral administration at a dose of 30 to 75 mg once a day for 10 days and did not isolate the virus initially, the frequency of laboratory-confirmed influenza decreased to 4% (2/47) compared with 21% (15/70) in the placebo group.
Prevention of influenza in immunocompromised individuals
In persons with weakened immunity during seasonal influenza infection and in the absence of virus release, the prophylactic use of Tamiflu reduced the frequency of laboratory-confirmed influenza infection, accompanied by clinical symptoms, to 0.4% (1/232) compared to 3% (7/231) in placebo group. Laboratory-confirmed influenza infection, accompanied by clinical symptoms,was diagnosed with an oral temperature above 37.2 ° C, cough and / or acute rhinitis (all recorded on the same day at the time of taking the drug / placebo), as well as a positive result of a reverse-transcriptase polymerase valuable reaction to influenza RNA.
Resistance Clinical researches
The risk of the emergence of influenza viruses with reduced sensitivity or resistance to the drug has been studied in clinical trials sponsored by Roche. Have
of all patients-carriers OK-resistant virus carrier was temporary, did not affect the elimination of the virus and did not cause a deterioration in the clinical state.
Population of Patients | Patients with mutations leading to resistance |
Phenotyping * | Geno-and phenotyping * |
Adults and teenagers | 4/1245 (0.32%) | 5/1245 (0.4%) |
Children (1-12 years old) | 19/464 (4.1%) | 25/464 (5.4%) |
miwir. The degree of decrease in sensitivity to oseltamivir and the frequency of occurrence of such viruses may differ depending on the season and the region. Resistance to oseltamivir is found in patients with pandemic influenza H1N1, who received the drug, both for treatment and for prevention.
The incidence of resistance may be higher in younger patients and in immunocompromised patients. Oseltamivir-resistant laboratory strains of influenza viruses and influenza viruses from patients treated with oseltamivir carry mutations of neuraminidase N1 and N2. Mutations that lead to resistance are often specific for the subtype of neuraminidase.
When deciding on the use of Tamiflu, the seasonal sensitivity of the influenza virus to the drug should be taken into account (the latest information can be found on the WHO website).
Preclinical data
Preclinical data obtained on the basis of standard studies on the study of pharmacological safety, genotoxicity and chronic toxicity, did not reveal a particular danger to humans.
Carcinogenicity: results of 3 studies on the detection of carcinogenic potential (two 2-year studies in rats and mice for oseltamivir and one 6-month study in transgenic mice Tg:AC for the active metabolite) were negative.
Mutagenicity: standard genotoxic tests for oseltamivir and the active metabolite were negative.
Impact on fertility: oseltamivir in a dose of 1500 mg / kg / day did not affect the generative function of male and female rats.
Teratogenicity: In studies on the teratogenicity of oseltamivir in a dose of up to 1500 mg / kg / day (in rats) and up to 500 mg / kg / day (rabbits), no effect on embryo-fetal development was detected. In studies on antenatal and postnatal developmental periods in rats, when oseltamivir was administered at a dose of 1500 mg / kg / day, there was an increase in the period of labor: the safety margin between exposure for humans and the maximum non-effecting dose in rats (500 mg / kg / day) for rats Oseltamivir is 480 times higher, and for its active metabolite 44 times. Exposure of the fetus was 15-20% of that of the mother.
Other: oseltamivir and active metabolite penetrate the milk of lactating rats. According to limited data oseltamivir and its active metabolite penetrate into
human breast milk. Based on the results of extrapolation of data obtained in studies in animals, their amount in breast milk can be 0.01 mg / day and 0.3 mg / day, respectively.
Approximately 50% of the guinea pigs tested, when the maximum doses of the active substance of oseltamivir were administered, skin sensitization in the form of erythema was observed.Also, reversible eye irritation in rabbits has been identified.
While very high oral single doses (657 mg / kg and above) of oseltamivir had no effect on adult rats, these doses had toxic effects on immature 7-day-old rats, including death of animals. Undesirable effects were not observed with chronic administration at a dose of 500 mg / kg / day from day 7 to day 21 of the postnatal period.