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Active ingredients
Oseltamivir
Release form
Capsules
Composition
One capsule contains: active substance: oseltamivir - 75 mg (in the form of oseltamivir phosphate - 98.5 mg); excipients: pregelatinized starch - 46.4 mg, povidone K30 - 6.7 mg, croscarmellose sodium - 3.4 mg, talc - 8.3 mg, sodium fumacyl fumarate - 1.7 mg; capsule shell - 63 mg (body - gelatin, iron dye black oxide (E172), titanium dioxide (E171); lid - gelatin, iron dye red oxide (E172), iron dye oxide yellow (E172), titanium dioxide ( E171)); ink for inscription on the capsule: ethanol, shellac, butanol, titanium di oxide (E171), aluminum lacquer based on indigo carmine, ethanol, denatured [methylated alcohol].
Pharmacological effect
Antiviral drug. Oseltamivir is a prodrug, its active metabolite (oseltamivir carboxylate, OK) is an effective and selective inhibitor of neuraminidase influenza A and B viruses - an enzyme that catalyzes the process of releasing newly formed virus particles from infected cells, their penetration into uninfected epithelial cells of the respiratory tract and further spread virus in the body. It inhibits the growth of the influenza virus in vitro and inhibits the replication of the virus and its pathogenicity in vivo, reduces the secretion of influenza A and B viruses from the body. The concentration of OC required for inhibiting neuraminidase by 50% (IC50) is 0.1-1.3 nM for influenza A virus and 2.6 nM for influenza B. The median IC50 values for influenza B virus are slightly higher and are 8.5 nM. Clinical efficacy of Tamiflu studies did not affect the formation of anti-influenza antibodies, including the production of antibodies in response to the introduction of inactivated influenza vaccine. Studies of natural influenza infection In clinical studies conducted during seasonal infection influenza, patients began receiving Tamiflu within 40 hours after the first symptoms of influenza infection. 97% of patients were infected with influenza A virus and 3% of patients with influenza B virus. Tamiflu significantly shortened the period of clinical manifestations of influenza infection (for 32 hours). In patients with a confirmed diagnosis of influenza who took Tamiflu, the severity of the disease, expressed as the area under the curve for the cumulative symptom index, was 38% less compared to patients who received a placebo.Moreover, in young patients without concomitant diseases, Tamiflu reduced by about 50% the incidence of complications of influenza, requiring the use of antibiotics (bronchitis, pneumonia, sinusitis, otitis media). Clear evidence was obtained of the drug's effectiveness with regard to secondary efficacy criteria related to antiviral activity: Tamiflu caused both a shortening of the virus excretion time and a reduction in the area under the “viral time-titer” curve. The data obtained in the Tamiflu therapy study in patients old and old age show that taking Tamiflu in a dose of 75 mg 2 times a day for 5 days was accompanied by a clinically significant decrease in the median of the period of clinical manifestations of influenza This infection is similar to that of adults in younger patients, but the differences did not reach statistical significance. In another study, patients with influenza older than 13 years who had concomitant chronic diseases of the cardiovascular and / or respiratory systems received Tamiflu under the same dosing regimen or placebo. There were no differences in the median of the period before the reduction of the clinical manifestations of influenza infection in the Tamiflu and placebo groups, however, the temperature rise period when taking Tamiflu decreased by about 1 day. The proportion of patients releasing the virus on the 2nd and 4th day 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 a fever (≥37.8 ° C) and one of the symptoms of the respiratory system (cough or rhinitis) during the period of circulation of the influenza virus among the population, a double-blind, placebo-controlled study was conducted. 67% of patients were infected with the influenza A virus and 33% of the patients with the influenza B virus. The drug Tamiflu (when taken no later than 48 hours after the first symptoms of influenza infection appeared) significantly reduced the duration of the disease (by 35.8 hours) compared to placebo. The duration of the disease was defined as the time to stop coughing, nasal congestion, disappearance of fever, and return to normal activity. In the group of children who received 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 who received Tamiflu compared to the placebo group. In another study, children aged 6-12 years old suffered from bronchial asthma; 53.6% of patients had influenza infection confirmed serologically and / or in culture. The median duration of illness in the group of patients treated with Tamiflu did not significantly decrease. But by the last 6 days of Tamiflu therapy, forced expiratory volume per 1 second (FEV1) increased by 10.8% compared with 4.7% in patients receiving placebo (p = 0.0148). Prevention of influenza in adults and adolescents Preventive efficacy of Tamiflu with natural influenza infection A and B have been proven in 3 separate phase III clinical studies. During the administration of Tamiflu, about 1% of patients fell ill with the flu. Tamiflu also significantly reduced the frequency of virus excretion and prevented the transmission of the virus from one family member to another. Adults and teenagers who were in contact with a sick family member started taking Tamiflu within two days after the onset of flu symptoms in family members and continued for 7 days, which significantly reduced the incidence of influenza in contact with people by 92%. In unvaccinated and generally healthy adults aged 18–65 years, taking Tamiflu during a flu epidemic significantly reduced the incidence of influenza ( 76%). Patients took the drug for 42 days. In elderly people who were in nursing homes, 80% of whom were vaccinated before the season when the study was conducted, Tamiflu significantly reduced the incidence of influenza by 92%. In the same study, Tamiflu significantly (by 86%) reduced the frequency of flu complications: bronchitis, pneumonia, sinusitis. Patients took the drug for 42 days. Prevention of influenza in children Preventive efficacy of Tamiflu in natural influenza infection was demonstrated in children from 1 year to 12 years after contact with a sick family member or someone from a permanent environment. The primary efficacy parameter was the frequency of laboratory confirmed influenza infection. In children who received Tamiflu / powder to prepare a suspension for oral administration / at a dose of from 30 to 75 mg once a day for 10 days and did not isolate the virus source,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 persons in immunocompromised individuals with seasonal influenza infection and in the absence of virus release, initial prophylactic use Tamiflu reduced the frequency of laboratory-confirmed influenza infection, accompanied by clinical symptoms, to 0.4% (1/232) compared to 3% (7/231) in the placebo group. Laboratory-confirmed influenza infection, accompanied by clinical symptoms, was diagnosed when there was an oral temperature above 37.2 ° C, cough and / or acute rhinitis (all registered on the same day while taking the drug / placebo), as well as a positive result of reverse transcriptase polymerase chain reaction for influenza virus RNA. Resistance Clinical Studies The risk of influenza viruses with decreased sensitivity or resistance to the drug was studied in clinical studies. vaniyah sponsored by Roche. In all patients with OK-resistant virus, the carrier had a temporary character, did not affect the elimination of the virus and did not cause a deterioration of the clinical condition. Patient population Patients with mutations leading to resistance Phenotyping * Genetic and phenotyping * Adults and adolescents 4/1245 (0.32%) 5/1245 (0.4%) Children (1-12 years old) 19/464 (4.1%) 25/464 ( 5.4%) * Full genotyping was not conducted in any of the studies. When taking Tamiflu for the purpose of post-exposure prophylaxis (7 days), prophylaxis of contacts in the family (10 days) and seasonal prophylaxis (42 days) in patients with normal function of the immune system, no cases of drug resistance were noted. In a 12-week study on seasonal prevention cases of immunocompromised cases of resistance were also not observed. The data of individual clinical cases and observational studies of patients who did not receive oseltamivir were found under natural conditions mutations Influenza A and B who have a reduced sensitivity to oseltamivir. In 2008, a mutation by the type of substitution H275Y, leading to resistance, was detected in more than 99% of the 2008 H1N1 virus strains circulating in Europe.The 2009 H1N1 influenza virus (“swine flu”) was in most cases sensitive to oseltamivir. Oseltamivir-resistant strains were found in individuals with normal immune system function and immunocompromised individuals taking oseltamivir. The degree of decrease in sensitivity to oseltamivir and the frequency of occurrence of such viruses may vary depending on the season and region. Resistance to oseltamivir was found in patients with pandemic H1N1 flu who received the drug for both treatment and prophylaxis. 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 receiving oseltamivir have mutations of N1 and N2 neuraminidase. Resistance-causing mutations are often specific for the neuraminidase subtype. When deciding whether to use Tamiflu, the seasonal sensitivity of the influenza virus to the drug should be taken into account (for the latest information, please see the WHO website). Clinical data obtained from standard pharmacological safety studies , genotoxicity and chronic toxicity, did not reveal any particular danger to humans. Carcinogenicity: results of 3 studies on the detection of cancer of ogeneous potential (two 2-year studies on rats and mice for oseltamivir and one 6-month study on transgenic Tg: AC mice for an active metabolite) were negative. Mutagenicity: standard genotoxic tests for oseltamivir and an active metabolite were negative. The effect on Fertility: oseltamivir at 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 at a dose of up to 1500 mg / kg / day (in rats) and up to 500 mg / kg / day (on Olika) effects on embryo-fetal development has not been found. In studies on the antenatal and postnatal periods of development in rats with the introduction of oseltamivir at a dose of 1500 mg / kg / day, an increase in the period of labor was observed: the safety limit between the exposure for humans and the maximum non-effect dose in rats (500 mg / kg / day) for 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 the active metabolite penetrate the milk of lactating rats. According to the limited data, oseltamivir and its active metabolite pass into the human breast milk. According to the results of extrapolation of the data obtained in animal studies, their amount in breast milk can be 0.01 mg / day and 0.3 mg / day, respectively. Approximately 50% of the tested guinea pigs with the introduction of maximum doses of the active substance oseltamivir showed sensitization of the skin in the form of erythema . Reversible eye irritation in rabbits was also detected. While very high oral single doses (657 mg / kg and higher) of oseltamivir did not affect adult rats, these doses had a toxic effect on immature 7-day-old rat pups, including to the death of animals. No adverse effects were observed with chronic administration at a dose of 500 mg / kg / day from 7 to 21 days of the postnatal period.
Pharmacokinetics
Osseltamivir absorption is easily absorbed in the gastrointestinal tract and is extensively converted into an active metabolite by the action of liver and intestinal esterases. The concentration of the active metabolite in plasma is determined within 30 minutes, the time to reach the maximum concentration of 2-3 hours, and more than 20 times the concentration of the prodrug. At least 75% of the ingested dose enters the systemic circulation in the form of the active metabolite, less than 5% in the form of the original drug. Plasma concentrations of both prodrugs and the active metabolite are proportional to the dose and do not depend on food intake. Distribution The distribution volume (Vss) of the active metabolite is 23 L. According to animal studies, after ingestion of oseltamivir, its active metabolite was detected in all major foci of infection (lungs, washing waters of the bronchi, mucous membrane of the nasal cavity, middle ear and trachea) in concentrations that provide antiviral effect. Communication of the active metabolite with plasma proteins - 3%. The association of prodrugs with plasma proteins is 42%, which is not enough to cause significant drug interactions. MetabolismOseltamivir is extensively converted into an active metabolite under the influence of esterases, which are primarily in the liver.Neither oseltamivir nor the active metabolite are substrates or inhibitors of isoenzymes of the cytochrome P450 system. Injection Exited (> 90%) as an active metabolite, mainly in the kidneys. The active metabolite does not undergo further transformation and is excreted by the kidneys (> 99%) by glomerular filtration and tubular secretion. Renal clearance (18.8 l / h) exceeds the glomerular filtration rate (7.5 l / h), which indicates that the drug is also excreted by tubular secretion. Less than 20% of the administered drug is excreted through the intestines. The half-life of the active metabolite is 6-10 hours.
Indications
Treatment of influenza in adults and children over the age of 1 year. Prevention of influenza in adults and adolescents over the age of 12 years who are in groups at increased risk of infection with the virus (in military units and large production teams, in debilitated patients). Prevention of influenza in children older 1 year.
Contraindications
Hypersensitivity to oseltamivir or any component of the drug. The terminal stage of renal failure (creatinine clearance of 10 ml / min). The child is under 1 year. Severe hepatic failure.
Precautionary measures
With care Pregnancy, breastfeeding period.
Use during pregnancy and lactation
Controlled studies in pregnant women have not been conducted. However, the results of post-marketing and observational studies have demonstrated the benefit of the proposed standard dosing regimen for this patient population. The results of the pharmacokinetic analysis showed a lower exposure to the active metabolite (approximately 30% during all trimesters of pregnancy) in pregnant women compared to non-pregnant women. However, the calculated exposure value remains above the inhibitory concentrations (IC95 value) and therapeutic values for many strains of influenza virus. Changing the dosage regimen in pregnant women is not recommended during therapy or prophylaxis (see the section “Pharmacokinetics in Special Groups of Patients”). No direct or indirect adverse effect of the drug on pregnancy, fetal fetal or postnatal development was found (see “Preclinical data”).When prescribing Tamiflu to pregnant women, both safety data and the course of pregnancy and the pathogenicity of the circulating influenza virus strain should be considered. Data on the excretion of oseltamivir with breast milk in humans and the use of oseltamivir by nursing women is limited. Oseltamivir and its active metabolite in small quantities penetrate into breast milk (see “Preclinical data”), creating subtherapeutic blood concentrations in an infant. When prescribing oseltamivir to lactating women, you should also take into account the comorbidity and pathogenicity of the circulating influenza virus strain. During pregnancy and during breastfeeding, oseltamivir is used only if the intended benefit to the mother outweighs the potential risk to the fetus and child.
Dosage and administration
Inside, with or without food. Tolerability can be improved by taking it with food. Adults, teenagers, or children who cannot swallow a capsule can also receive Tamiflu treatment in the dosage form “powder for suspension for oral administration”. In cases where Tamiflu “Powder for suspension for oral administration” is absent, or if there are signs of “aging” of capsules (for example, increased fragility or other physical disturbances), it is necessary to open the capsule and empty it. boiled in a small amount (max 1 teaspoon) of suitable sweetened food (chocolate syrup with normal or no sugar content, honey, light brown sugar or table sugar dissolved in water, sweet dessert, sweetened condensed milk, applesauce or yogurt) in order to hide the bitter taste. The mixture must be thoroughly mixed and given to the patient as a whole. Swallow the mixture immediately after preparation. Detailed recommendations are given in the subsection "Extemporal preparation of Tamiflu Suspension."Increasing the dose of more than 150 mg / day does not increase the effect. Children weighing> 40 kg or between the ages of 8 and 12 Children who can swallow capsules can also receive treatment, taking 75 mg one capsule 2 times a day. for 5 days. Children from 1 to 8 years old. Tamiflu powder is recommended for preparing a suspension for oral administration of 12 mg / ml or capsules of 30 and 45 mg (for children over 2 years old). To determine the recommended dosing regimen, see the Tamiflu powder for medical use instructions for the preparation of a suspension for oral administration of 12 mg / ml or 30 and 45 mg capsules. It is possible to prepare the preparation of suspensions using 75 mg capsules (see the subsection “The preparation of the preparation of Tamiflu suspension”). Prevention: The drug should be started no later than 2 days after contact with patients. Adults and adolescents aged 312 yearsTo 75 mg once a day inside for at least 10 days after contact with the patient. During the seasonal flu epidemic, 75 mg once a day for 6 weeks. The prophylactic effect lasts as long as the drug is taken. Children weighing> 40 kg or between the ages of 8 and 12. Children who can swallow capsules can also receive preventive therapy, taking 75 mg one capsule 1 time per day for 10 days.Children from 1 year to 8 years old. Tamiflu powder is recommended for the preparation of a suspension for oral administration of 12 mg / ml or 30 and 45 mg capsules. To determine the recommended dosing regimen, see the Tamiflu powder for medical use instructions for the preparation of a suspension for oral administration of 12 mg / ml or 30 and 45 mg capsules. It is possible to prepare the suspension with the use of capsules 75 mg (see the section “The preparation for the preparation of Tamiflu suspension”). Dosing in special cases Patients with kidney damage Treatment of patients with creatinine clearance more than 60 ml / min dose adjustment is not required. In patients with creatinine clearance from 30 to 60 ml / min, the dose of Tamiflu should be reduced to 30 mg twice a day for 5 days. In patients with creatinine clearance from 10 to 30 ml / min, the dose of Tamiflu should be reduced to 30 mg once a day for 5 days. Patients on constant hemodialysis, Tamiflu in the initial dose of 30 mg can be taken before dialysis, if the symptoms of flu appear within 48 hours between dialysis sessions. To maintain the plasma concentration at the therapeutic level, Tamiflu should be taken at 30 mg after each session of dialysis.For patients on peritoneal dialysis, Tamiflu should be taken in an initial dose of 30 mg before starting dialysis, then 30 mg every 5 days (see also "Dosing in special cases" and "Special instructions"). The pharmacokinetics of oseltamivir in patients with end-stage renal disease (with creatinine clearance ≤ 10 ml / min) who are not on dialysis has not been studied. In this regard, there are no recommendations for dosing in this group of patients. Prevention Patients with creatinine clearance of more than 60 ml / min do not require dose adjustment. In patients with creatinine clearance from 30 to 60 ml / min, the dose of Tamiflu should be reduced to 30 mg once a day. In patients with creatinine clearance from 10 to 30 ml / min, it is recommended to reduce the dose of Tamiflu to 30 mg every other day. Patients on permanent hemodialysis, Tamiflu in the initial dose of 30 mg can be taken before the start of dialysis ("1st session"). To maintain the plasma concentration at the therapeutic level, Tamiflu should be taken at 30 mg after each subsequent odd dialysis session. For patients on peritoneal dialysis, Tamiflu should be taken in an initial dose of 30 mg before dialysis, then 30 mg every 7 days (see also "Dosing in special cases" and "Special instructions"). The pharmacokinetics of oseltamivir in patients with end-stage renal disease (with creatinine clearance ≤ 10 ml / min) who are not on dialysis has not been studied. In this regard, there are no recommendations for dosing in this group of patients. Patients with liver damage. Dose adjustment in the treatment and prevention of influenza in patients with mild and moderately impaired liver function is not required. Safety and pharmacokinetics of Tamiflu in patients with severely impaired liver function has not been studied. Patients of old and old ageDose adjustment for the prevention or treatment of influenza is not required. Patients with weakened immunity (after transplantation) For seasonal prevention of influenza in patients with weakened immunity aged ≥1 years - within 12 weeks, the dose adjustment is not required (see the section "Dosage and administration"). ChildrenTamiflu in this dosage form should not be administered to children under 1 year.
Side effects
In adult / adolescent influenza treatment studies, nausea, vomiting, and headache were the most common adverse reactions (HPs). Most of the HPs occurred on the first or second day of treatment and were on their own within 1-2 days. In studies on the prevention of influenza in adults and adolescents, the most common HP was nausea, vomiting, headache and pain. Vomiting was the most common in children. Described HP in most cases did not require discontinuation of the drug. Treatment and prevention of influenza in adults and adolescents Table 1 presents the most frequent HP (≥1%) when taking the recommended dose of Tamiflu in studies on the prevention and treatment of influenza in adults and adolescents mg 2 times a day for 5 days for treatment and 75 mg 1 time per day for up to 6 weeks for prophylaxis), and the frequency of which is at least 1% higher compared to placebo. Influenza treatment studies included adults / adolescents without comorbidities and patients at risk, i.e. patients with a high risk of developing complications of influenza (elderly and elderly patients, patients with chronic heart or respiratory diseases). In general, the safety profile of patients at risk corresponded to that of adults / adolescent patients without comorbidities. Further, adverse events that occurred with a frequency of ≥1% in adults and adolescents who received oseltamivir as therapy and prevention of influenza infection are presented. These adverse events were either more frequently observed in patients receiving placebo, or differences in frequency between the oseltamivir and placebo groups were less than 1%: Disorders of the gastrointestinal tract (Tamiflu vs. placebo): treatment - diarrhea (6% against 7%) , abdominal pain (including pain in the upper abdomen, 2% versus 3%); prevention - diarrhea (3% versus 4%), pain in the upper abdomen (2% versus 2%), dyspepsia (1% versus 1% ) .Infections and invasions (Tamiflu vs. placebo): treatment - bronchitis (3% versus 4%), sinusitis (1% versus 1%), herpes simplex (1% versus 1%); prevention - nasopharyngitis (4% versus 4%), upper respiratory tract infections (3% versus 3%), influenza infection (2% versus 3%). General disorders (Tamiflu vs. placebo): treatment - dizziness (including vertigo, 2% versus 3%); prevention - fatigue (7% vs. 7%),pyrexia (2% versus 2%), flu-like illness (1% versus 2%), dizziness (1% versus 1%), pain in the limb (1% versus 1%). Nervous system disorders (Tamiflu versus placebo): treatment - insomnia (1% vs. 1%); prevention - insomnia (1% vs. 1%). Violations of the respiratory system, chest organs and mediastinum (Tamiflu against placebo): treatment - cough (2% vs. 2%), nasal congestion (1% vs 1%); prevention - nasal congestion (7% vs 7%), sore throat (5% vs 5%), cough (5% vs 6%), rhinorrhea (1% vs 1%). Violations from the side with muscular and connective tissue (Tamiflu vs. placebo): prevention - back pain (2% versus 3%), arthralgia (1% versus 2%), myalgia (1% versus 1%). Violations of the genital and lactic glands (Tamiflu versus placebo): prevention - dysmenorrhea (3% versus 3%). Treatment and prevention of influenza infection in elderly and elderly Safety profiles in 942 elderly and senile patients who received Tamiflu or placebo were not clinically different from those in young age (up to 65 years). Prevention of influenza Noa infection in patients with weakened immunityIn a 12-week study on the prevention of influenza involving 475 patients with weakened immunity (including 18 children aged 1 to 12 years), in patients who took Tamiflu (n = 238), the safety profile corresponded to the previously described in studies on the prevention of influenza. Treatment and prevention of influenza infection in children without comorbidities aged 1-12 years and patients with bronchial asthmaIn studies on the treatment of natural influenza infection in children aged 1 g An ode to 12 years of age with oseltamivir (n = 858), with a frequency of ≥1% and at least 1% more than placebo (n = 622), was vomiting. Children who received the recommended dose of Tamiflu 1 time day as post-exposure prophylaxis at home, vomiting was most common (8% in the group of oseltamivir versus 2% in the group not receiving prophylactic treatment). Tamiflu was well tolerated, reported adverse events were as previously described when treating influenza in children. Further, adverse events were noted in children with a frequency ≥1% in influenza treatment studies (n = 858) or with a frequency ≥5% in prevention studies influenza (n = 148).These adverse events were more frequently observed in the placebo / no prophylaxis group, the differences between oseltamivir and placebo / no prophylactic groups were less than 1%. Disorders of the gastrointestinal tract (Tamiflu vs. placebo): treatment - diarrhea (9% vs. 9%) , nausea (4% vs. 4%), abdominal pain (including pain in the upper abdomen, 3% versus 3%). Infections and invasions (Tamiflu against placebo): treatment - otitis media (5% vs. 8%), bronchitis (2% versus 3%), pneumonia (1% versus 3%), sinusitis (1% versus 2%). Respiratory disorders the national system, organs of the chest and mediastinum (Tamiflu vs. placebo): treatment - asthma (including exacerbation, 3% versus 4%), nosebleeds (2% versus 2%); prevention - cough (12% versus 26%), congestion nasal (11% versus 20%). Disorders of the skin and subcutaneous tissues (Tamiflu vs. placebo): treatment - dermatitis (including allergic and atopic dermatitis, 1% versus 2%). Disorders of the organ of hearing and labyrinth disorders (Tamiflu against placebo): treatment - earache (1% vs. 1%). Violations on the part of the organ of vision (Tamiflu against the parade ebo): treatment - conjunctivitis (including eye redness, eye discharge and eye pain, 1% vs. <1%). Additional adverse events noted during the treatment of influenza in children that did not meet the above criteria. Blood disorders and lymphatic system (Tamiflu vs. placebo): treatment - lymphadenopathy (<1% vs. 1%). Impairment of the organ of hearing and labyrinth disorders (Tamiflu vs. placebo): treatment - damage to the eardrum (<1% vs. 1%). Postmarketing observationMore are presented adverse effects of Tamiflu observed during post-marketing surveillance. The frequency of these adverse events and / or causal relationship with the use of the drug Tamiflu cannot be established because the true size of the population is not known due to the voluntary nature of the messages. Disorders of the skin and subcutaneous tissues: hypersensitivity reactions - dermatitis, skin rash, eczema , urticaria, erythema multiforme exudative, Stevens-Johnson syndrome and toxic epidermal necrolysis, allergies, anaphylactic and anaphylactoid reactions,Quincke's edema. Violations of the liver and biliary tract: hepatitis, an increase in the activity of "liver" enzymes in patients with flu-like symptoms who received Tamiflu; fulminant hepatitis (including fatal outcomes), liver failure, jaundice. Neuropsychiatric Disorders Influenza infection may be associated with various neurological symptoms and behavioral changes, including symptoms such as hallucinations, delusions and abnormal behavior. In some cases, they can be fatal. Such phenomena can occur both against the background of the development of encephalopathy or encephalitis, and without the manifestation of these diseases. Patients (mainly children and adolescents) who took Tamiflu for the treatment of influenza had convulsions and delirium (including symptoms like , disorientation in time and space, abnormal behavior, delusions, hallucinations, agitation, anxiety, nightmares). These cases were rarely accompanied by life-threatening actions. The role of Tamiflu in the development of e